bims-engexo Biomed News
on Engineered exosomes
Issue of 2026–05–31
77 papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Therapeutically Engineering Exosomes to Target CD206+ M2 Macrophages to Prevent the Development of Primary Tumors and Distal Metastases in Breast Cancers.
  2. The molecular language: decoding exosomal cargoes in macrophage-gastric cancer dialogue.
  3. Exosome-mediated post-transcriptional oncogene regulation as a novel cancer therapeutic strategy.
  4. Harnessing exosomes for biomarker development and therapy in hepatitis virus infection.
  5. Biolayer Interferometry-Based Detection of Engineered Extracellular Vesicles Binding to Type I Collagen.
  6. Bioinspired polydopamine interfacial engineering of plant-derived exosomes enhances doxorubicin bioactivity in 2D and 3D breast cancer models.
  7. Cell Membrane Vesicles Encapsulating Il24 mRNA With Enriched CD6 Display Exhibit Enhanced Targeted Antitumor Efficacy.
  8. Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.
  9. Exosomal miR-373-3p Derived from Docetaxel-Resistant Lung Cancer Cells Targets PDCD4 to Promote Proliferation and Inhibit Apoptosis in Lung Cancer Cells.
  10. Engineered Plant-Derived Extracellular Vesicles: A Novel Strategy for Tumor-Targeted Therapy.
  11. Nature-inspired nanodiscs for lesion-targeted delivery reprogram macrophages and attenuate established abdominal aortic aneurysms.
  12. Tendon dECM Composited with Chitosan with Loading Skin Precursor Stem Cell Exosome for Enhanced Diabetic Wound Healing.
  13. Bio inspired assessment of titanium-organic framework and exosome-constructed p-Synephrine carriage: pursuing the PI3K/mTOR pathway in a simulated periodontitis.
  14. Breaking the vicious cycle of diabetic wounds with an exosome-engineered dual-responsive microneedle patch.
  15. M1 macrophage-targeted engineered ginseng stems and leaves-derived extracellular vesicles delivery system for alleviating rheumatoid arthritis.
  16. Jujuboside A-Loaded Exosomes Alleviate Pulmonary Fibrosis via TGF-β/Smad and Autophagy Regulation.
  17. Fucoidan-based smart micelles enable P-selectin-targeted and ROS-responsive delivery of mitochonic acid 5 for mitochondrial functional improvement in acute lung injury.
  18. A photo-responsive, fisetin-functionalized DNA nanocage for programmed therapy to accelerate early-stage wound healing in aged skin.
  19. Leveraging engineered small EVs to mitigate cancer pain: a new paradigm.
  20. Stem Cell-Derived Exosomes in Wound Healing and Skin Regeneration: Emerging Therapeutic Strategies and Mechanisms.
  21. Rhizomes as Multi-Target Pharmacological Platforms Against Tauopathy: Neuro-Metabolic Crosstalk, Drug-Likeness, and Translational Challenges.
  22. Macrophage membrane-biomimetic nanoparticles for targeted delivery of melatonin in myocardial ischemia-reperfusion injury.
  23. MSC-Derived Apoptotic Vesicles Restore Bone Marrow Niche Homeostasis in Postmenopausal Osteoporosis by miRNA-Mediated Suppression of MAPK and NF-κB Signaling Nodes.
  24. Kaempferol-modified mesenchymal stem cell extracellular vesicle-mimetics promote photoaging repair by suppressing ADAM10.
  25. Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.
  26. Arginine Polymer-Based Nanoplatform Facilitates Oral Co-Delivery of Antibody/Antigen for Robust Oral Immunotherapy in Orthotopic Colon Cancer.
  27. A Covalently Engineered Metal-Organic Framework Nanosystem for Imaging-Guided Photoimmunotherapy of Metastatic Tumors.
  28. Graphene Oxide Quantum Dots-Loaded Extracellular Vesicles with Inflamed Pulp-Homing Targeting Enhance Pulp Repair in Pulpitis by Upregulating Glycolysis.
  29. The Trojan Horse system composed of platelet membrane and extracellular vesicles inhibits atherosclerotic plaque progression.
  30. Corrigendum to "Functional engineered mesenchymal stem cells with fibronectin‑gold composite coated catheters for vascular tissue regeneration" [Nanomed: Nanotechnol Biol Med 14 (2018) 699-711].
  31. A Comparative Analysis of iPSC, MSC, and 293T-Derived Exosomes for Parkinson's Disease Therapy.
  32. Adipocytes and macrophages after stroke: Interactions between metabolism and immunity.
  33. Characterization of exosomes from hypoxia-activated human amniotic membrane mesenchymal stem cells.
  34. Bacterial Membrane Vesicles as Versatile Platforms for Systemic and Mucosal Vaccines.
  35. Gelatin Methacryloyl Hydrogels as a Multifaceted Platform for Promoting Nerve Regeneration.
  36. Exosome-loaded nanoradiosensitizers in radiotherapy for preventing post-irradiation tumor recurrence: mechanisms, preclinical evidence, and translational challenges.
  37. Extracellular vesicles for diabetes and its complications: Harnessing mammalian and plant sources from direct interventions to engineered applications.
  38. Biomimetic lung-targeting vehicle coupled with cryo-shocked leukocyte and inflammation-anchored liposome for drug delivery and anti-inflammation in treatment of acute pneumonia.
  39. Engineering RVG-modified exosomes for targeting TGF-β1 signaling in stroke recovery.
  40. Macrophage exosome-modified Mn/Se nanoheterostructure induces post-infarction cardiomyocyte regeneration and immunometabolic microenvironment repair.
  41. Hydrogel-exosome synergistic system: mechanisms, applications and future prospects in regenerative medicine.
  42. Exosome mediated crosstalk in gastrointestinal cancers progression: special focus on Integrin β3 as a cargo.
  43. Structure-Guided Engineering of Histidine-Rich pH-Switchable Endosomolytic Peptides for Spleen-Selective siRNA Delivery to Inflammatory Macrophages.
  44. Use of Exosomes as Adjuvant Therapy in the Reconstruction of Traumatic Eyelid Wounds: A Case Report.
  45. Recombinant Spider Silk Enhances Engineered Cartilage Formation.
  46. Desmoplasia and therapeutic resistance in pancreatic ductal adenocarcinoma.
  47. Digital droplet microfluidics integrating DNA walkers and CRISPR-Cas13a for simultaneous surface protein and miRNA profiling in single exosomes.
  48. Endogenous Engineering Reprograms Extracellular Vesicles for Enhanced Therapeutic Function.
  49. Endolysins, Depolymerases, Holins, and VALs: Phage-Derived Proteins for Combating Antimicrobial Resistance.
  50. Synergistic engineering of a GRAS-certified strain: Transforming Bacillus subtilis 168 into a high-performance nicotine scavenger.
  51. Cracking the shield: oncolytic viruses versus the tumor-immune fortress.
  52. Advances of Cell Membrane-Coated Nanotechnology and Membrane Vesicles in Intestinal Targeted Drug Delivery Systems.
  53. Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.
  54. Engineered Bacillus subtilis secreting piscidin-1/hepcidin enhances resistance against Aeromonas hydrophila in a zebrafish model.
  55. Diabetes-Driven Post-Translational Remodeling in Pancreatic Ductal Adenocarcinoma.
  56. The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders.
  57. DNA-Targeted Sonodynamic Activation Enhances Antibacterial Efficacy in Deep and Hypoxic Infections.
  58. Engineered nanomedicine triggering ROS storms for enhanced cancer therapeutics.
  59. Nano-armed bcg delivers Cu-Fe MOF to trigger dual cell death in bladder cancer.
  60. An optimised lipid nanoparticle platform enables efficient CRISPR/Cas9 genome editing in hard-to-transfect cells.
  61. Novel Mechanistic Insights into Primary Biliary Cholangitis: From Pathogenesis to Mesenchymal Stem Cell-Mediated Repair.
  62. Gene therapy, RNA-based drugs, and CRISPR in neuroprotection.
  63. Sotorasib combined with 3-methyladenine for the treatment of KRAS G12C-mutant pancreatic cancer and its underlying mechanisms.
  64. Exosome-mimetic nanocarriers in cancer diagnosis and drug delivery: engineering strategies, functional biomimicry, safety considerations, and clinical translation.
  65. Recent Advancements and Applications of Quantum Dots in Tissue Engineering.
  66. Dual-functional poly(disulfide) enables "Once-and-for-all" atherosclerosis therapy via precision hepatocyte base editing.
  67. Discovery and Characterization of Interleukin-4-Specific Affibodies for Affinity-Controlled Protein Release and Macrophage Polarization.
  68. A multifunctional nanobooster to restore ceftazidime susceptibility in mucoid Pseudomonas aeruginosa.
  69. An in situ generated CAR-M with IFN-γ and negative dominance Sirpα isoform augments hepatocellular carcinoma immunotherapy.
  70. Photodynamic Therapy Improves Sensitivity to Temozolomide in Glioblastoma Cells via Inhibiting Autophagy.
  71. Stimuli-responsive microneedles: Engineered solutions for multifaceted diabetic wound healing.
  72. Modularly designed hybrid vesicles as dual-adjuvant nanovaccines for cancer immunotherapy.
  73. Engineering human T cells with antigen receptors for immune regulation in autoimmune disease and transplantation.
  74. A novel auto-fluorescent porphyrin-lipid nanoparticle strategy for CTNNB1 gene silencing in hepatocellular carcinoma.
  75. Middle-Term Follow-Up Outcomes of the Customised Temporomandibular Joint-Skull Base Combined Prosthesis by 3D Printing.
  76. Hormone-optimized hypocotyl-epicotyl-cotyledonary tri-complex explant system enables efficient soybean transformation with reduced genotype dependence.
  77. I-TEP: A Simple and Affordable Method to Measure Permeability in Reconstructed Tissues Combined with DAMO-TSC-Based Urea Assay.
  1. Cancers (Basel). 2026 May 16. pii: 1619. [Epub ahead of print]18(10):
    Therapeutically Engineering Exosomes to Target CD206+ M2 Macrophages to Prevent the Development of Primary Tumors and Distal Metastases in Breast Cancers.
    Mahrima Parvin, Ahmet Alptekin, Sawaiz Kashif, Fowzia A Selina, Mst Anika Bushra, Mohammad Syam, Mohammad H Rashid, Alicia Arnold, Yutao Liu, Santhakumar Manicassamy, Hasan Korkaya, Ali S Arbab.
      Background/objective: Approximately 90% of breast cancer-related deaths result from recurrence and metastasis. Emerging evidence indicates that tumor recurrence, invasion, and metastatic spread are strongly influenced by both the tumor microenvironment (TME) and the metastatic niche. M2 macrophages promote immune suppression, inhibit inflammation, and facilitate epithelial-to-mesenchymal transition, invasion, neovascularization, and tumor progression. These phenomena are particularly pronounced in triple-negative breast cancer (TNBC). The objectives of this study were to develop engineered exosomes to selectively deplete CD206+ M2 macrophages from the TME to delay the growth of primary tumors and distal metastasis and enhance overall survival. Methods: Engineered exosomes were developed using our invented platform to selectively target and deplete alternatively activated CD206+ M2 macrophages in primary and metastatic TMEs via antibody-dependent cell-mediated cytotoxicity (ADCC). The engineered exosomes were characterized for size, zeta potential, and successful incorporation of targeting peptides and proteins. Whole-body and tumor-specific biodistribution were assessed. In vitro and in vivo experiments were conducted to evaluate targeting specificity. Toxicity and immunogenicity were examined in immunocompetent animal models. Two treatment paradigms were employed. Results: Engineered exosomes containing M2 macrophage-targeting peptides and Fc-mIgG2b were successfully made, and no significant size difference was observed between the engineered and control exosomes. Both in vitro and in vivo studies confirmed the specificity of the engineered exosomes. Biodistribution studies showed no significant uptake or retention by the resident macrophages in the lung and liver. No significant immune activation, based on cytokine profiling, or organ-specific toxicity was observed in immunocompetent models. Flow cytometry studies using splenocytes showed significant depletion of M2 macrophages following treatments with engineered exosomes; however, no effect on the distribution of T cells was observed. M2-targeting engineered exosomes significantly delayed the post-resection recurrence and metastasis of tumors, and improved animal survival. Conclusions: These findings support the potential of precision exosome-based strategies for enhancing therapeutic outcomes in breast cancer.
    Keywords:  antibody-dependent cellular cytotoxicity; breast cancer; exosomes; tumor associated macrophages; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18101619
  2. Biochim Biophys Acta Rev Cancer. 2026 May 24. pii: S0304-419X(26)00087-9. [Epub ahead of print] 189615
    The molecular language: decoding exosomal cargoes in macrophage-gastric cancer dialogue.
    Jianjun Wang, Yilin Sun, Xiaowei Su, Yiping Xie, Bei Ye, Xiuping Wang, Lingxiang Mao, SongGong, Hui Qian.
      Exosomes mediate a two-way signaling between gastric cancer (GC) cells and macrophages in the tumor microenvironment (TME) and have significant effects on tumor progression, immune suppression, and treatment outcomes. This paper will bring together existing literature on the vesicular cargo of macrophage-derived and GC-derived exosomes, such as non-coding RNAs (ncRNAs), and proteins, and their contribution to the re-polarization of macrophages, as well as the behavior of GC cells. The cargo contained in macrophage-derived exosomes biases signaling pathways associated with macrophage polarization, tumor-promoting phenotype, and helping GC proliferation, invasion, metastasis, and chemoresistance. Conversely, macrophage exosomal messages may complement anti-tumor immunity through the regulation of PD-L1 and augmentation of T cells. The exosomes of GC also remodel the macrophage phenotype in favor of immunosuppression by delivering cargoes, facilitating metabolic reprogramming, and tumor-associated macrophages (TAMs) polarization. This crosstalk is generalized to more widespread tumor stroma interactions, which involve cancer-associated fibroblasts (CAFs) and angiogenesis. The resulting therapeutic implications are engineered exosomes and cargo-modified vesicles to tip the balance towards anti-tumor immunity and overcome chemoresistance, where a high efficiency of loading and precision of targeting remain problematic, and the translation of preclinical research findings to the clinic.
    Keywords:  TAM; exosomes; gastric cancer; macrophages; ncRNAs; polarization
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189615
  3. Discov Oncol. 2026 May 23.
    Exosome-mediated post-transcriptional oncogene regulation as a novel cancer therapeutic strategy.
    Bunty Sharma, Kawaljit Singh Kaura, Ranjay Kumar Choudhary, Suresh Babu Kondaveeti, Malathi Hanumanthayya, Abhishek Chauhan, Sanjana Gupta, Himanshu Sharma, Anuj Ranjan, Ambrish Mishra, Ujjawal Sharma.
      Exosomes are tiny vesicles (30-150 nm in size) secreted by nearly every cell type that have lately emerged as essential regulators of intercellular communication and gene expression in cancer. They accommodate bioactive cargos such as miRNAs, lncRNAs, circRNAs, and mRNAs, all of which direct oncogene expression at the post-transcriptional level. Exosomal RNAs influence post-transcriptional and epigenetic regulatory mechanisms implicated in tumor activity, including mRNA degradation, translation repression and activation, alternative splicing interference, and epigenetic remodeling, which contribute to tumorigenic processes such as proliferation, angiogenesis, metastasis, immune evasion, and drug resistance. Tumor-derived exosomes also regulate the key oncogenic pathways such as PI3K/AKT, JAK/STAT, and Wnt/β-catenin to promote tumor stroma remodeling, thereby inducing macrophage M2 polarization, fibroblast transformation into cancer-associated fibroblasts, and pre-metastatic niche formation, favoring metastases. Targeting exosome-mediated oncogenic communication has therapeutic potential. Strategies include inhibiting exosome biogenesis and release using GW4869 or blocking Rab GTPases, blocking exosome uptake, and modulating oncogenic RNA cargo using antisense oligonucleotides, RNA interference, or CRISPR/Cas13-mediated RNA editing. Engineered exosomes also serve as natural, biocompatible carriers for the therapeutic delivery of siRNAs, miRNA mimics, mRNAs, or CRISPR components, offering improved stability, specificity, and reduced immunogenicity compared to synthetic counterparts. There are significant translational challenges, including large-scale manufacturing, purification, standardization, and biosafety testing, despite promising preclinical and early clinical results. In summary, comprehending and implementing post-transcriptional oncogene regulation via exosomes is a transformative strategy in precision oncology, creating new opportunities in targeted diagnosis, prognostication, and advanced cancer therapies.
    Keywords:  Exosomes; Oncogene modulation; Post-transcriptional regulation; Tumor microenvironment; lncRNA; miRNA
    DOI:  https://doi.org/10.1007/s12672-026-05255-y
  4. Clin Chim Acta. 2026 May 23. pii: S0009-8981(26)00291-3. [Epub ahead of print]591 121109
    Harnessing exosomes for biomarker development and therapy in hepatitis virus infection.
    Kurbaniyazova Madina Zafarjanovna, Alidjanova Lazizakhon Abbasovna, Toshov Hayot Muhammadovich, Ismailov Uktam, Nurova Go'zal Ubaydullayevna, Nazarova Mokhira Azamatovna, Nazarova Nodira, Kenjayev Sardor, Tulkin Alimboevich Matkurbanov, Alibek Botirkul Ogli Jabborov, Ibroximjon Xasanov, Suban Xusanov, Firuzjon Farkhodjonovich Muydinov.
      Exosomes, a specialized subclass of extracellular vesicles, have emerged as critical mediators in the pathogenesis of viral hepatitis. Hepatotropic viruses hijack host exosomal biogenesis pathways to facilitate immune evasion, promote viral dissemination, and drive chronic inflammation and hepatic fibrosis. Paradoxically, these same vesicles offer unprecedented opportunities for noninvasive disease monitoring and targeted therapeutic intervention. This narrative review synthesizes current evidence on the dual role of exosomes in hepatitis virus infection, evaluating their evolution from pathogenic vectors to clinical tools for liquid biopsy diagnostics and engineered antiviral delivery. We examined how exosomal cargo, including microRNAs, proteins, and viral nucleic acids, enables precise stratification of liver disease stages, real-time treatment monitoring, and early detection of hepatocellular carcinoma. Furthermore, we explore advanced bioengineering strategies, such as endogenous cargo loading, surface functionalization, and the targeted delivery of CRISPR/Cas9 complexes and RNA-based therapeutics, which position engineered exosomes as next-generation precision nanomedicines. Despite compelling preclinical data, clinical translation remains constrained by significant bottlenecks, including scalable good manufacturing practice (GMP) production, the lack of standardized isolation and characterization protocols, and evolving regulatory pathways. Bridging the gap between laboratory innovation and bedside application will require coordinated advancements in manufacturing technology, global standardization initiatives, and rigorous clinical validation. Successfully overcoming these hurdles could establish exosome-based platforms as transformative tools for achieving functional cures and improving long-term outcomes in patients with viral hepatitis.
    Keywords:  Biomarker discovery; Engineered therapeutics; Exosomes; Liquid biopsy; Viral hepatitis
    DOI:  https://doi.org/10.1016/j.cca.2026.121109
  5. Anal Biochem. 2026 May 28. pii: S0003-2697(26)00118-1. [Epub ahead of print] 116162
    Biolayer Interferometry-Based Detection of Engineered Extracellular Vesicles Binding to Type I Collagen.
    Yan-Jing Zhang, Yinchan Wang, Xuemei Chen, Shuaishuai Yu, Jingyuan Yang, Lin Cheng, Jing Cui, Sisi Wu.
      Engineered extracellular vesicles (EVs) have garnered significant attention due to their potential serving as both therapeutic agents and drug delivery vehicles. Real-time monitoring of engineered EVs-target interactions constitutes a critical need for advancing EVs-based therapeutics. Here, we present a novel biolayer interferometry (BLI)-based analytical platform for detecting dynamic interactions between collagen-binding domain (CBD)-engineered EVs and type I collagen (Col I). A stable CD63-CBD fusion protein-expressing mouse tendon cell line (designated TT-D6sCBD cells) was initially established using a lentiviral transduction system. Engineered EVs (TT-D6sCBD-EVs) were subsequently isolated through optimized differential ultracentrifugation. Col I was covalently immobilized on AR2G biosensors for detecting EVs binding using BLI technology. Quantitative analysis revealed that TT-D6sCBD-EVs-treated biosensors demonstrated significantly enhanced BLI signals versus control group (TT-D6sVec-EVs), along with time-dependent signal accumulation. Correlative microscopy validation-including scanning electron microscopy (SEM) and confocal microscopy imaging-confirmed the enhanced EVs binding capacity in the test group compared to controls. This work establishes a paradigmatic methodology for characterizing binding kinetics between engineered EVs and their molecular targets, offering critical technical support for advancing precision EVs-based therapeutics.
    Keywords:  Binding interactions; Biolayer Interferometry; Engineered extracellular vesicles; Type I collagen; collagen-binding domain
    DOI:  https://doi.org/10.1016/j.ab.2026.116162
  6. Biomater Adv. 2026 May 25. pii: S2772-9508(26)00270-0. [Epub ahead of print]187 214972
    Bioinspired polydopamine interfacial engineering of plant-derived exosomes enhances doxorubicin bioactivity in 2D and 3D breast cancer models.
    Ghazal Khosravani, Shiva Irani, Reza Mirfakhraie, Saeed Beigi-Boroujeni, Fereshteh Sharifi.
      Plant-derived exosomes have emerged as promising bioinspired nanomaterials for drug delivery; however, limited control over their surface interactions and therapeutic behavior restricts their functional potential. Herein, we introduce a bioinspired interfacial engineering strategy that simultaneously integrates polydopamine (PDA) surface engineering and doxorubicin loading through a one-step ultrasonic assembly process. This approach enables tunable regulation of exosome surface chemistry, colloidal stability, and drug retention without compromising nanoscale architecture. The engineered exosomes exhibit a uniform size of 179.2 nm (PDI = 0.303) and high encapsulation efficiency (85.8%), while demonstrating suppressed premature drug leakage under physiological conditions (19% cumulative release at pH 7.4 over 7 days) and accelerated release in acidic environments. More importantly, PDA-mediated surface modulation significantly alters exosome-cell interactions, resulting in enhanced cellular internalization and amplified apoptosis in MCF-7 and MDA-MB-231 breast cancer cells. In physiologically relevant 3D tumor models based on electrospun polycaprolactone/chitosan hydrogel droplet scaffolds, PDA-engineered exosomes reduce the IC₅₀ of doxorubicin to 36.7 μM compared with 88.3 μM for free drug, while maintaining reduced cytotoxicity toward normal fibroblasts. These results demonstrate that polydopamine-based interfacial engineering improves the stability, release behavior, and therapeutic bioactivity of plant-derived exosome nanocarriers, supporting their potential application in advanced in vitro cancer treatment models.
    Keywords:  3D tumor model; Bioactive nanomaterials; Breast cancer therapy; Plant-derived exosomes; Polydopamine (PDA) coating; pH-responsive drug delivery
    DOI:  https://doi.org/10.1016/j.bioadv.2026.214972
  7. J Extracell Vesicles. 2026 Jun;15(6): e70299
    Cell Membrane Vesicles Encapsulating Il24 mRNA With Enriched CD6 Display Exhibit Enhanced Targeted Antitumor Efficacy.
    Dandan Wang, Ruofan Gao, Duo Liu, Kefan Li, Runkai Wang, Minghe Xu, Shiwei Zhang, Shengjie Jiang, Bin Xia.
      mRNA-based therapeutics offer significant potential for cancer treatment owing to their ability to induce transient, non-integrating expression of therapeutic proteins. However, effective and tumour-specific delivery remains a major barrier. In this study, we report a cell membrane vesicle (CMV)-based delivery platform for targeted mRNA therapy, employing engineered CMVs enriched with the surface molecule CD6 for the selective delivery of Il24 mRNA to CD166-overexpressing tumour cells. CMVs were derived from NIH-3T3 cells via cytochalasin B induction and genetically modified to express CD6, enabling biomimetic targeting through the CD6-CD166 axis. Il24 mRNA was loaded into CD6-CMVs through a digitonin-assisted permeabilisation strategy, achieving high encapsulation efficiency and sustained intracellular release. In vitro, CD6-CMVs facilitated enhanced uptake in CT26 cells, leading to elevated IL-24 expression, activation of apoptotic and autophagic pathways, and suppression of migration and invasion. In mouse colorectal cancer and squamous carcinoma models, CD6-CMVs/Il24 mRNA demonstrated effective tumour targeting, increased intratumoral IL-24 translation, and potent antitumor efficacy, with minimal off-target accumulation or systemic toxicity. Notably, this treatment promoted immune cell infiltration and reshaped the tumour microenvironment towards a pro-inflammatory state. This study presents a scalable, low-immunogenicity CMV platform capable of targeted mRNA delivery and cytokine expression, offering a promising strategy for precision immunotherapy for solid tumours.
    Keywords:  anti‐tumour; cell membrane vesicles; il24 MRNA; targeted therapy
    DOI:  https://doi.org/10.1002/jev2.70299
  8. J Nanobiotechnology. 2026 May 23.
    Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.
    Lufei Chen, Xiaoling Lin, Mingzhi Fu, Shenglang Chen, Zhexiao Yan, Yuelin Diao, Genyu Chen, Zichen Huang, Yan Sun, Yaxin Lin, Zucheng Ye, Ying Zhou, Qinyong Ye.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.
    Keywords:  Exosome; Parkinson’s disease; Peptide; Pyrroloquinoline quinone; α-synuclein
    DOI:  https://doi.org/10.1186/s12951-026-04552-6
  9. Biomedicines. 2026 Apr 25. pii: 986. [Epub ahead of print]14(5):
    Exosomal miR-373-3p Derived from Docetaxel-Resistant Lung Cancer Cells Targets PDCD4 to Promote Proliferation and Inhibit Apoptosis in Lung Cancer Cells.
    Yuan Yuan, Buyi Zhu, Linfei Yang, Yumu Leng, Feifei Chen, Zhenhua Yang, Wei Gu, Kai Zhang.
      Background: Lung cancer ranks among the most common and deadly malignant tumors worldwide. Drug resistance is a critical factor hindering the effect of chemotherapy for lung cancer. Exosomes, as intercellular signaling molecule carriers, play an important role in carcinogenesis, metastasis and drug resistance. Our study was aimed at exploring the impact of exosomes derived from docetaxel (DTX)-resistant lung cancer cells on regulating biological behaviors of DTX-sensitive cells, further investigating the molecular mechanisms regarding exosome-mediated intercellular communication. Methods: We extracted and identified the exosomes derived from A549, A549/DTX, H1299 and H1299/DTX cells, and then analyzed the expression of exosomal miR-373-3p between DTX-sensitive and DTX-resistant cells. Cell proliferation and apoptosis experiments were verified using a CCK-8 assay, a colony formation assay, a TUNEL assay and flow cytometry. The molecular interaction between miR-373-3p and PDCD4 was evaluated using a dual-luciferase reporter assay. The function of miR-373-3p was further assessed using an in vivo mouse xenograft model. Results: We found that the exosomal miR-373-3p level from DTX-resistant A549/DTX or H1299/DTX cells significantly exceeded that from DTX-sensitive A549 or H1299 cells. In addition, both exosomes derived from DTX-resistant lung cancer cells and miR-373-3p mimics could promote the proliferation of DTX-sensitive cells and inhibit their apoptosis. Moreover, we identified PDCD4 as a key target gene of miR-373-3p, which could induce the malignant behaviors of DTX-sensitive cells by reducing PDCD4 expression. Conclusions: Our results demonstrated that DTX-resistant lung cancer cells could transfer miR-373-3p to DTX-sensitive cells through exosomes, where miR-373-3p could exert its carcinogenic effect via targeting PDCD4.
    Keywords:  PDCD4; docetaxel resistance; exosome; lung cancer; miR-373-3p
    DOI:  https://doi.org/10.3390/biomedicines14050986
  10. Pharmaceutics. 2026 May 07. pii: 577. [Epub ahead of print]18(5):
    Engineered Plant-Derived Extracellular Vesicles: A Novel Strategy for Tumor-Targeted Therapy.
    Yuan Zuo, Jinying Zhang, Xinxin Wang, Bo Sun, Shuo Tian, Mingsan Miao.
      Cancer remains a leading cause of premature death worldwide, posing a significant burden due to its high incidence and mortality. Radiotherapy and chemotherapy remain the most well-established and effective modalities in the current oncological therapeutic arsenal. However, their efficacy is often limited by toxicities owing to their non-selective targeting of rapidly dividing cells and consequent damage to healthy tissues. In recent years, advances in nanomedicine and biotechnology have drawn increasing attention to plant-derived extracellular vesicles (PDEVs) as an emerging, promising strategy for cancer therapy. As novel therapeutic vehicles, PDEVs offer key advantages, including high biocompatibility and low immunogenicity. However, their clinical translation has been significantly hampered by inherent limitations, including insufficient targeting specificity, low and uncontrollable drug-loading efficiency, and challenges in large-scale production and standardization. Current research is actively focused on overcoming these drawbacks through engineering strategies, for instance, surface modification with targeting peptides or antibodies to enhance targeting, alongside optimization of production and drug-loading processes. These developments underscore the potential of PDEVs as a promising platform for next-generation targeted cancer therapeutics. This review provides a comprehensive overview of PDEVs, covering their isolation, biogenesis, physicochemical properties, and anticancer applications. While summarizing these fundamental aspects, this review focuses on engineering strategies to enhance their active targeting capacity, offering theoretical insights to support their future role in cancer treatment.
    Keywords:  artificial bionic; cancer; covalent and noncovalent modifications; drug delivery; engineered plant-derived exosome-like nanovesicles; nanocarriers; surface modification
    DOI:  https://doi.org/10.3390/pharmaceutics18050577
  11. bioRxiv. 2026 May 16. pii: 2026.05.13.724870. [Epub ahead of print]
    Nature-inspired nanodiscs for lesion-targeted delivery reprogram macrophages and attenuate established abdominal aortic aneurysms.
    Zhongshan He, Yitao Huang, Yinghui Wang, Qian Ren, Junchao Xu, Qiaochu Wang, Lian-Wang Guo, Huan Bao.
      Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by chronic inflammation and immune dysregulation, with lesional macrophages playing a pivotal role in disease progression. However, effective and safe delivery of immune modulators to macrophages at the site of AAA remains a major clinical challenge. To address this unmet need, we report a nature-inspired nanodisc platform based on high-density lipoproteins for targeted delivery to lesional macrophages, further engineered with a multi-component targeting strategy incorporating an aneurysm-homing peptide and phosphatidylserine lipids. Nanodiscs encapsulating an anti-inflammatory protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor remarkably attenuated progression of established AAA in an elastase-induced mouse model. Using a combination of in vivo biodistribution and immune profiling approaches, we demonstrate that nanodisc-assisted PERK inhibitor delivery selectively reprograms the local immune microenvironment and attenuates pathological inflammation in AAA disease models. Notably, a single administration achieves sustained therapeutic efficacy with favorable safety profiles, effectively limiting the progression of established AAA in a clinically relevant setting. This work presents a new avenue of designer nanomedicines for targeted immunomodulation and maybe broadly applicable for a wide range of vascular and immune-mediated pathologies.
    DOI:  https://doi.org/10.64898/2026.05.13.724870
  12. Gels. 2026 Apr 26. pii: 361. [Epub ahead of print]12(5):
    Tendon dECM Composited with Chitosan with Loading Skin Precursor Stem Cell Exosome for Enhanced Diabetic Wound Healing.
    Yunguang Chen, Yingying Liang, Yaling Deng, Lei Nie.
      Diabetic wounds are a common and severe complication of diabetes mellitus, characterized by delayed healing due to persistent inflammation, impaired angiogenesis, and cellular dysfunction. Conventional therapeutic approaches remain limited in efficacy. In recent years, exosomes have attracted considerable attention in wound healing and regenerative medicine because of their crucial role in intercellular communication and tissue repair. However, rapid clearance of exosomes in vivo greatly limits their therapeutic efficacy. To address this critical limitation, we engineered a decellularized extracellular matrix (dECM)-based hydrogel system functionalized with exosomes derived from skin-derived precursor cells (SKPs). This biomimetic scaffold was designed to serve as a local exosome-delivery platform at the wound site, with the aim of improving exosome utilization and augmenting their regenerative effects. Comprehensive in vitro characterization demonstrated that the exosome-loaded composite hydrogels exhibited robust pro-angiogenic activity, as evidenced by enhanced endothelial cell proliferation, migration, and tube formation. Moreover, the hydrogels displayed significant antibacterial effects against wound-relevant pathogens and potent reactive oxygen species (ROS)-scavenging capacity, thereby mitigating oxidative damage. Notably, the composite hydrogels also promoted the phenotypic polarization of macrophages toward the pro-regenerative M2 phenotype. In parallel, in vivo studies using a streptozotocin-induced diabetic rat wound model confirmed that treatment with the composite hydrogels significantly accelerated wound closure rates compared to control groups. Histological and immunohistochemical analyses revealed enhanced angiogenesis, as evidenced by increased CD31-positive microvessel density, as well as improved collagen deposition, re-epithelialization, and an attenuated local inflammatory microenvironment characterized by reduced pro-inflammatory cytokine expression and elevated M2 macrophage infiltration. Collectively, the SKPs exosome-loaded dECM based composite hydrogels developed in this study represent a potential therapeutic strategy for the treatment of diabetic wounds.
    Keywords:  angiogenesis; diabetic wounds; exosome; hydrogel
    DOI:  https://doi.org/10.3390/gels12050361
  13. Sci Rep. 2026 05 25. pii: 16133. [Epub ahead of print]16(1):
    Bio inspired assessment of titanium-organic framework and exosome-constructed p-Synephrine carriage: pursuing the PI3K/mTOR pathway in a simulated periodontitis.
    Mohamed S Kishta, Abdelrahman H Elshaar, Rawan N Makled, Ghada A Abdel-Aleem, Mirhan N Makled, Reda M Abdelhameed.
      Periodontitis, a chronic inflammatory disease, is driven by bacterial infection and oxidative stress, leading to tissue destruction and potential tooth loss. This study investigates the anti-inflammatory and antioxidant potential of p-Synephrine and enhanced delivery through NH2-MIL-125 and exosomes derived from dental pulp stem cells (DPSCs). Primary Normal Human Gingival Keratinocytes (PCS) and Gingival Fibroblasts (HGF) were divided into eight groups, including controls, induction with LPS, and treatments with NH2-MIL-125, exosomes, free p-Synephrine, p-Synephrine-loaded NH2-MIL-125 (P-SYN-NH2-MIL-125), p-Synephrine-loaded exosomes (P-SYN-Exo), and dexamethasone as a reference drug. Pro-inflammatory cytokines (IL-4, IL-6, TNF-α) and pathway markers (PI3K and mTOR) were quantified using ELISA kits, while antioxidant enzyme activities (GPx, SOD, and TAC) were assessed using colorimetric assays. Results showed that p-Synephrine loaded into NH2-MIL-125 reduced inflammation markers and enhanced antioxidant defenses by increasingof GPx, SOD, and TAC concentrations. Among all treatments, p-Synephrine-loaded exosomes (P-SYN-Exo) demonstrated the most significant results, showing the highest increase in antioxidant markers GPx, SOD, and TAC, alongside a pronounced reduction in pro-inflammatory cytokines IL-4, IL-6, and TNF-α. Furthermore, p-Syn-Exo exhibited the most marked decrease in signaling pathway markers PI3K and mTOR. NH2-MIL-125 and exosomes amplified these effects through controlled release and improved bioavailability, demonstrating superior reductions in TNF-α, IL-4, and IL-6 and increased antioxidative stress markers. These findings highlight p-Synephrine, particularly when delivered via NH2-MIL-125 and exosomes, as a promising adjunctive treatment for periodontal inflammation and oxidative stress.
    Keywords:  Dental pulp stem cells (DPSCs); Exosomes; MIL-125; Periodontitis; p-Synephrine
    DOI:  https://doi.org/10.1038/s41598-026-54070-6
  14. Mater Today Bio. 2026 Jun;38 103198
    Breaking the vicious cycle of diabetic wounds with an exosome-engineered dual-responsive microneedle patch.
    Xinyu Gu, Shen Shen, Qingmiao Shi, Ziyi Xu, Minghang Zhang, Lifan Zhang, Chen Xue, Yuting He, Juan Lu, Li Li.
      Diabetic wound (DW), a prevalent type of chronic non-healing injury, poses substantial clinical challenges owing to persistent oxidative stress, dysregulated inflammation and recurrent bacterial infections. To rationally modulate the microenvironment of DWs, this study fabricated a core-shell structured multifunctional microneedle (MN) patch, designated as AEP-GCMN. Specifically, we designed engineered exosomes, Aloe-ExoPC (AEP), by encapsulating proanthocyanidins (PC) into aloe-derived exosomes, which were then integrated into methacrylated hyaluronic acid (HAMA) to serve as the core layer of the MN patch. In contrast, a polyvinyl alcohol/polyvinylpyrrolidone (PVA/PVP) blend was loaded with catalase (CAT) and surface-functionalized with Gold Nano-Stars (GNS), forming the structural shell of the patch. The AEP-GCMN patch operates through a multi-stage mechanism: its casing rapidly produces oxygen via CAT upon wound contact, while the embedded GNS enable photothermal antibacterial therapy under NIR light. Subsequently, the sustained release of AEP leads to the intracellular delivery of PCs, which alleviate oxidative stress and inhibit inflammation to improve the microenvironment. Additionally, Aloe-Exos contribute to angiogenesis and cell migration. This intelligent responsive system offers a synergistic strategy for the temporal modulation of hypoxia, infection and chronic inflammation in DWs, representing a promising intelligent therapeutic approach for DW management.
    Keywords:  Anti-inflammation; Diabetic wounds; Exosomes; Microneedles
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103198
  15. Regen Biomater. 2026 ;13 rbag078
    M1 macrophage-targeted engineered ginseng stems and leaves-derived extracellular vesicles delivery system for alleviating rheumatoid arthritis.
    Chuanjie Zhang, Yingjie Wang, Xiaoyu Jiang, Dake Wang, Yajiang Yuan, Jianye Li, Weiran Gao, Housen Jiang, Xifan Mei.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, oxidative stress damage and joint destruction. Current treatments often face challenges including limited targeting efficacy and systemic side effects. To develop a novel targeted therapy for RA, this study constructed a functionalized extracellular vesicle (EV) system by engineering ginseng stems and leaves-derived EVs with hyaluronic acid (HA) modification and curcumin (Cur) loading (Cur@EVs-PH). Structurally, the EVs-PH drug-loaded nanoplatform integrates the remarkable anti-inflammatory and antioxidant properties of EVs with the prolonged circulation capacity conferred by PEG. This design further capitalizes on the targeting ability of HA, thereby providing a robust structural foundation for the efficient delivery of therapeutics to disease sites. Our results demonstrated that the designed system achieved enhanced inflammatory targeting through CD44 receptor-mediated accumulation and exhibited potent anti-inflammatory and antioxidant activities. In the collagen-induced arthritis model, Cur@EVs-PH significantly alleviated joint swelling, reduced pathological scores and normalized immune organ indices. Mechanistic studies revealed that the therapeutic effects were mediated through suppression of pro-inflammatory cytokines and promotion of macrophage M2 polarization. This integrated strategy combining natural EVs, targeted modification and active drug loading provides a promising platform for the treatment of RA and other inflammatory diseases.
    Keywords:  CD44; macrophage; plant-derived extracellular vesicles; rheumatoid arthritis; targeted drug delivery
    DOI:  https://doi.org/10.1093/rb/rbag078
  16. Tissue Eng Part A. 2026 May 23. 19373341261449902
    Jujuboside A-Loaded Exosomes Alleviate Pulmonary Fibrosis via TGF-β/Smad and Autophagy Regulation.
    Jing Liu, Shuli Zhang, Yi Sun, Minghao Gu, Xuedong Liu.
      This study aimed to scrutinize the antifibrotic effects of jujuboside A-loaded exosomes (JuA-Exo) on TGF-β1-induced MRC-5 fibroblasts and explore the pathophysiological basis. Exosomes were isolated from human mesenchymal stem cells and loaded with JuA by ultrasonic dispersion. A TGF-β1-induced MRC-5 fibrosis model was established. Cell viability, migration capacity, levels of inflammatory cytokines, extracellular matrix components, and autophagy-related markers were assessed. To determine autophagy dependence, the autophagy inhibitor 3-methyladenine (3-MA) was employed. JuA-Exo significantly attenuated fibroblast activation triggered by TGF-β1, decreased the secretion of IL-6, IL-1β, and hydroxyproline, and downregulated fibrotic gene expression, including α-SMA, fibronectin, COL1A1, and COL3A1. Mechanistically, JuA-Exo was associated with modulation of the TGF-β/Smad signaling pathway and restoration of autophagy-related markers. Importantly, the defensive effects of JuA-Exo were reversed upon autophagy inhibition by 3-MA. JuA-Exo exerts antifibrotic and anti-inflammatory effects, which are associated with modulation of TGF-β/Smad signaling and autophagy-related processes; however, the mechanistic linkage between these pathways and their causal roles requires further validation. These findings highlight JuA-Exo as a potential experimental candidate, although the current evidence is limited to in vitro observations and does not yet support therapeutic application.Impact StatementThis study demonstrates that jujuboside A-loaded exosomes exert antifibrotic and anti-inflammatory effects in vitro, providing mechanistic insight and highlighting a potential nanotherapeutic approach that warrants further validation.
    Keywords:  TGF-β/Smad signaling; autophagy; exosomes; jujuboside A; pulmonary fibrosis
    DOI:  https://doi.org/10.1177/19373341261449902
  17. Int J Biol Macromol. 2026 May 26. pii: S0141-8130(26)02674-7. [Epub ahead of print] 152747
    Fucoidan-based smart micelles enable P-selectin-targeted and ROS-responsive delivery of mitochonic acid 5 for mitochondrial functional improvement in acute lung injury.
    Ye-Fei Ruan, Jin-Hui Wang, Wen-Da Zhong, Lin Qiu.
      Acute lung injury (ALI) is a life-threatening condition with complex pathogenesis. Mitochondrial dysfunction in pulmonary vascular endothelial cells serves as a central hub, driving oxidative stress, inflammation, and barrier disruption. Existing treatments are limited by poor targeting and insufficient efficacy. To address this, we engineered a novel dual-targeting nanoplatform, P-selectin-directed and ROS-responsive fucoidan micelles loaded with the mitochondrial modulator Mitochonic Acid 5 (Fuc-TP@MA-5). Here we show that this system actively homes to inflamed lung endothelium via fucoidan-P-selectin binding and selectively releases MA-5 within the high-ROS microenvironment via thioketal linker cleavage. This enhanced delivery potently restores mitochondrial membrane potential and ATP production, scavenges excess ROS, and inhibits endothelial apoptosis. Consequently, Fuc-TP@MA-5 significantly attenuates pulmonary edema, vascular hyperpermeability, and inflammatory cytokine storm in a murine model of LPS-induced ALI, outperforming free MA-5. Our work establishes a targeted mitochondrial functional improvement strategy, offering a promising and intelligent nanotherapeutic paradigm for treating ALI and other vascular inflammatory disorders.
    Keywords:  Acute lung injury; Micelles; Mitochonic acid 5; P-selectin; Vascular endothelial cells
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152747
  18. Biomaterials. 2026 May 21. pii: S0142-9612(26)00354-6. [Epub ahead of print]334 124330
    A photo-responsive, fisetin-functionalized DNA nanocage for programmed therapy to accelerate early-stage wound healing in aged skin.
    Ziqi Yue, Zhou Jiang, Yichen Yang, Wumeng Yin, Yunfeng Lin, Yang Gao, Xiaoxiao Cai.
      Age-related impaired wound healing presents distinct challenges compared to conventional wounds, primarily due to dysregulated phase kinetics of wound repair and chronic cellular senescence, which collectively disrupt the dynamic and orderly progression of tissue regeneration. Effective intervention requires a stage-specific and temporally programmed therapeutic strategy. To address this, we first performed transcriptome sequencing (RNA-seq) to elucidate the differential healing trajectory between young and aged wounds. Herein, we construct a photo-responsive, Fisetin-functionalized DNA nanocage (TAF) for spatiotemporally precise therapy of aged wounds. TAF is composed of a tetrahedral DNA nanocage loaded with a miR-29-targeting antisense oligonucleotide (ASO) covalently linked through a photocleavable linker and noncovalently encapsulating the senolytic agent Fisetin. The TAF platform enables a programmed therapeutic strategy: (a) the intrinsic antioxidant capacity of DNA scavenges excessive reactive oxygen species (ROS) during the early inflammatory phase; (b) photo-triggered ASO release in the proliferative phase promotes collagen synthesis; and (c) sustained Fisetin release eliminates senescent cells, fostering a pro-regenerative microenvironment. In vivo studies in aged mice reveal that TAF-mediated therapy significantly accelerates early wound closure and enhances high-quality tissue regeneration. In summary, TAF establishes an efficient nanomedicine platform that improves aged tissue repair through stage-specific, temporally programmed regulation.
    Keywords:  Aged tissue repair; DNA nanostructures; Photoactivatable; Senolytic; microRNA-29
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124330
  19. J Microencapsul. 2026 May 28. 1-21
    Leveraging engineered small EVs to mitigate cancer pain: a new paradigm.
    Subham Sarkar, Souvik Roy, Lopamudra Choudhury.
       BACKGROUND: Cancer pain is a complex, debilitating symptom involving both nociceptive mechanisms from tissue damage, tumour acidification, and pro-inflammatory mediators, and neuropathic components from tumour invasion, chemo- or radiation-induced nerve injury, altered ion channels, and glial activation. This peripheral and central sensitisation makes conventional analgesics inadequate and toxic.
    OBJECTIVES AND METHODOLOGY: Engineered small extracellular vesicles (EVs) can offer a promising nanomedicine solution. These biocompatible, nanoscale vesicles cross biological barriers, including the blood-brain barrier, and can be loaded with therapeutic cargo like anti-inflammatory miRNAs, neurotrophic factors, or analgesics via parent cell engineering or direct loading and functionalization.
    CONCLUSION: Targeted EV delivery can enable localised suppression of pro-nociceptive inflammation, nerve repair, precise analgesic release, and tumour burden reduction, addressing cancer pain's molecular mechanisms for more effective pain relief.
    Keywords:  Cancer; central sensitisation; engineered small extracellular vesicles; neuropathic components; nociceptive mechanisms
    DOI:  https://doi.org/10.1080/02652048.2026.2677813
  20. Cells. 2026 May 10. pii: 872. [Epub ahead of print]15(10):
    Stem Cell-Derived Exosomes in Wound Healing and Skin Regeneration: Emerging Therapeutic Strategies and Mechanisms.
    Nithin Vidiyala, Pavani Sunkishala, Prashanth Reddy Parupathi, Dinesh Nyavanandi.
      Chronic cutaneous wounds and traumatic skin injuries remain a major clinical challenge, characterized by dysregulated healing phases, high susceptibility to microbial infection, and suboptimal response to conventional therapies. Stem cell-derived exosomes (SC-Exos) have emerged as a paradigm-shifting, cell-free nanotherapeutic platform that harnesses the paracrine secretome of stem cells while avoiding the immunological and proliferative complications inherent to direct cell transplantation. Exosomes derived from diverse stem cell sources orchestrate multifactorial wound repair by modulating key cellular signaling cascades and transcriptomic programs that collectively regulate inflammation, angiogenesis, re-epithelialization, extracellular matrix (ECM) remodeling, and scar formation. Beyond their intrinsic regenerative capacity, SC Exos can be engineered using direct strategies (cargo loading, surface modification, biomaterial integration, and conjugation) and indirect approaches (genetic engineering, pretreatment, and preconditioning of parental cells), thereby enabling spatially controlled and temporally sustained exosome release at wound sites with enhanced bioavailability and therapeutic efficacy. In parallel, biomaterial-assisted delivery platforms, including hydrogels, scaffolds, and nanofibers, enhance exosome retention, stability, and controlled-release profiles within the wound microenvironment, thereby further potentiating tissue repair. This review provides a comprehensive overview of recent advances in SC Exos for wound healing and skin regeneration. We first summarize exosome biogenesis, molecular composition, and the distinctive characteristics of exosomes derived from different stem cell sources, along with preclinical evidence supporting their efficacy in cutaneous repair. We then critically examine exosome engineering strategies and biomaterial-integrated delivery systems that augment and fine-tune therapeutic outcomes. Finally, we discuss the current status of clinical trials of SC Exo-based therapies, key manufacturing and regulatory challenges, and future directions for translating these nanoscale, cell-free therapeutics into advanced, personalized wound management.
    Keywords:  biomaterial integration; chronic wound healing; mesenchymal stem cells; nanomedicine; skin regeneration; stem cell-derived exosomes
    DOI:  https://doi.org/10.3390/cells15100872
  21. Pharmaceuticals (Basel). 2026 May 19. pii: 792. [Epub ahead of print]19(5):
    Rhizomes as Multi-Target Pharmacological Platforms Against Tauopathy: Neuro-Metabolic Crosstalk, Drug-Likeness, and Translational Challenges.
    Andreas Wilson Setiawan, Jinwon Choi, Sohyun Park, Min Choi, Raymond Rubianto Tjandrawinata, Edwin Hadinata, Moon Nyeo Park, Taruna Ikrar, Fahrul Nurkolis, Bonglee Kim.
      Tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse "multi-target platforms" whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from "single-compound optimism" to network pharmacology with translational discipline.
    Keywords:  CNS drug-likeness; multi-target pharmacology; neuro-metabolic crosstalk; rhizomes; tauopathy
    DOI:  https://doi.org/10.3390/ph19050792
  22. Nanomedicine. 2026 May 27. pii: S1549-9634(26)00063-8. [Epub ahead of print] 102962
    Macrophage membrane-biomimetic nanoparticles for targeted delivery of melatonin in myocardial ischemia-reperfusion injury.
    Tian Huang, Zewei Zhang, Ruoyu Hou, Baoyi Lin, Dingtao Wang, Guogang Xu.
      Myocardial ischemia-reperfusion injury (MIRI) remains a major clinical challenge following the restoration of blood flow after ischemic events in the heart. Excessive reactive oxygen species production during this process exacerbates cellular damage and impairs cardiac function. However, clinically effective and safe antioxidative treatments are yet to be developed. Melatonin is a potential endogenous antioxidant with widely reported protective effects against cardiac damage and altered physiology during I/R injury, yet its short circulation half-life and insufficient accumulation at injured sites restrict its therapeutic efficacy. To address these limitations, we developed a liposome-based biomimetic nanoparticle (NPs@MM) consisting of a liposome and a macrophage membrane shell. By inheriting the intrinsic inflammatory tropism of macrophages, NPs@MM selectively targeted injured vascular endothelium and accumulated in ischemic myocardial tissue. Moreover, melatonin release was triggered by the acidic environment at the infarcted site, enabling effective scavenging of excess ROS. The amount of NPs@MM in the infarcted myocardium was greatly increased compared with NPs alone, resulting in an effective reduction of the MIRI-induced ROS. Collectively, these findings suggest that NPs@MM enable targeted delivery of melatonin and effective attenuation of oxidative stress in the MIRI region, thereby protecting the myocardium from ROS-induced damage.
    Keywords:  Biomimetic; Myocardial ischemia-reperfusion injury; Targeted anti-inflammatory therapy
    DOI:  https://doi.org/10.1016/j.nano.2026.102962
  23. Pharmaceuticals (Basel). 2026 May 15. pii: 777. [Epub ahead of print]19(5):
    MSC-Derived Apoptotic Vesicles Restore Bone Marrow Niche Homeostasis in Postmenopausal Osteoporosis by miRNA-Mediated Suppression of MAPK and NF-κB Signaling Nodes.
    Zhiwen Tu, Haolin Wu, Youxi Jiang, Xinxin Li, Zhiqing Huang, Songtao Shi, Ruibao Ren.
      Background: Postmenopausal osteoporosis is associated with cellular senescence and the accumulation of the senescence-associated secretory phenotype (SASP). While mesenchymal stem cell (MSC)-derived exosomes show tissue repair potential, the efficacy and mechanisms of MSC-derived apoptotic vesicles (apoVs) remain unclear. This study compared MSC-apoVs and exosomes in postmenopausal osteoporosis and investigated the underlying epigenetic mechanisms. Methods: Therapeutic efficacy was evaluated in an ovariectomized (OVX) mouse model and senescent human bone marrow mesenchymal stem cells (hBMMSCs). Small RNA sequencing identified differential microRNA (miRNA) cargos between vesicle types. SASP-related cytokine expression (IL-6, TNF-α, MCP-1) and pathway activation were assessed by RT-qPCR, ELISA, and Western blot. Results: MSC-apoV treatment attenuated bone loss in OVX mice and reduced SASP expression in senescent hBMMSCs to a greater extent than exosomes. Small RNA sequencing revealed that apoVs were enriched with a specific miRNA cluster, including hsa-let-7b-5p, hsa-miR-92a-3p, and hsa-miR-98-5p. Bioinformatic analyses identified BRAF and CRKL as downstream targets of this miRNA cluster, supported by reduced protein levels after apoV treatment. Subsequent molecular assays showed that apoV treatment inhibited the phosphorylation of both the MAPK (p38 and JNK) and NF-κB (p65) signaling pathways, which correlated with reduced local inflammation in the bone marrow microenvironment and preserved osteogenic differentiation capacity. Conclusions: MSC-apoVs attenuate postmenopausal osteoporosis more effectively than exosomes. This enhanced efficacy is associated with the delivery of an enriched miRNA cluster that inhibits MAPK and NF-κB signaling, together with suppression of BRAF and CRKL protein expression. ApoVs may represent a cell-free therapeutic strategy for age-related bone loss.
    Keywords:  apoptotic vesicles; bone marrow mesenchymal stem cells; exosomes; microRNA; osteoporosis; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.3390/ph19050777
  24. Cell Commun Signal. 2026 May 27.
    Kaempferol-modified mesenchymal stem cell extracellular vesicle-mimetics promote photoaging repair by suppressing ADAM10.
    Nan Fu, Huan Zhang, Xianhao Shi, Xian Xiao, Xiaoxia Li, Ping Song, Shihua Wang, Robert Chunhua Zhao.
      Chronic ultraviolet B (UVB) exposure accelerates skin photoaging by inducing excessive reactive oxygen species (ROS), inflammation, and extensive extracellular matrix (ECM) degradation. Increasing evidence indicates that extracellular vehicles (EVs) derived from mesenchymal stem cells (MSCs) hold promise for mitigating skin photoaging; however, the low yield of naturally secreted EVs poses a significant challenge to their clinical scalability. To overcome this barrier, we generated MSC-derived extracellular vesicle mimetics (MSC-EVMs), which preserved the bioactivity of EVs while enabling high-efficiency production. We further engineered a hybrid nanoplatform-MSC-EVM@Kae-by loading kaempferol (Kae), a natural inhibitor of the ECM-degrading protease ADAM10 with strong antioxidative and anti-inflammatory properties.MSC-EVM@Kae markedly reduced ROS accumulation, DNA damage, and cellular senescence in UVB-irradiated fibroblasts and keratinocytes, while restoring MMP/TIMP homeostasis through ADAM10 suppression. In a UVB-induced photoaging mouse model, microneedle-assisted transdermal delivery of MSC-EVM@Kae significantly improved wrinkle severity, enhanced collagen deposition, and reinforced epidermal barrier integrity.Collectively, our findings demonstrate that kaempferol-loaded MSC-EVM integrate the inherent regenerative potential of MSC-derived vesicles with the pharmacological inhibition of ADAM10, offering a scalable and bioengineered strategy for combating UVB-induced photoaging. This hybrid system provides a promising foundation for next-generation, cell-free therapeutics targeting skin aging and oxidative stress-related disorders.
    Keywords:  ADAM10; Extracellular vesicles; Kaempferol; Mesenchymal stem cells; Mimetics; Photoaging
    DOI:  https://doi.org/10.1186/s12964-026-02940-x
  25. Animal Model Exp Med. 2026 May 26.
    Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.
    Waheeb Sami Aggad, Rakesh Ghosh, Hailah M Almohaimeed, Zuhair M Mohammedsaleh, Fayez M Saleh, Amany I Almars, S Renuka Jyothi, Rajashree Panigrahi, Ajoy Kumer, Bikram Dhara.
      The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.
    Keywords:  Alzheimer's disease; Parkinson's disease; blood–brain barrier; exosomes; extracellular vesicles; gut–brain axis; microRNA; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.1002/ame2.70226
  26. ACS Nano. 2026 May 27.
    Arginine Polymer-Based Nanoplatform Facilitates Oral Co-Delivery of Antibody/Antigen for Robust Oral Immunotherapy in Orthotopic Colon Cancer.
    Yali Zhuang, Liying Wang, Chunyuan Xie, Ruoxi Yang, Minghui Li, Chunlei Dai, Yongxiang Di, Mengfang Yuan, Tong Tong, Tianren Zhang, Xinru You, Xiaojun Xia, Jun Wu.
      Immune checkpoint blockade and therapeutic cancer vaccines have transformed cancer treatment, yet their clinical application in colorectal cancer remains constrained by the lack of efficient oral delivery strategies for biomacromolecules such as antibodies and protein antigens. Here, we report a smart oral immunotherapy strategy that enables the codelivery of programmed death-ligand 1 antibody (anti-PD-L1) and ovalbumin (OVA) antigen for localized colorectal cancer treatment through an arginine-based polymeric nanoplatform. A biosafe cationic arginine-derived polymer (2A6S) was rationally engineered to electrostatically load both antibody and antigen cargos, while an enteric polymer coating (EudragitL100) protected the nanocomplexes from gastric degradation and ensured intestinal release. This dual-protective oral platform (EAPO NPs) achieved efficient colon lesion delivery and significantly enhanced local antitumor immune activation in an orthotopic MC38-OVA colorectal tumor model. Encouragingly, oral administration of EAPO NPs induced 53.34% tumor inhibition using only twice the antibody/antigen dosage compared with systemic injection, while substantially reducing potential systemic immunotoxicity. By integrating immune checkpoint blockade with antigen-specific immune priming through a single oral nanoplatform, this work establishes a simple, safe, and effective strategy for localized intestinal immunotherapy, which could be applicable to colorectal cancer and other colon-associated diseases.
    Keywords:  arginine-based poly(ester amide)s; immunotherapy; oral delivery; orthotopic colorectal tumors; protein delivery
    DOI:  https://doi.org/10.1021/acsnano.6c08006
  27. ACS Appl Mater Interfaces. 2026 May 29.
    A Covalently Engineered Metal-Organic Framework Nanosystem for Imaging-Guided Photoimmunotherapy of Metastatic Tumors.
    Jiangsheng Li, Wei Jin, Hongbo Wang, Shiyi Zhai, Benchao Zheng, Weiping Gao, Xunbin Wei, Kuangda Lu.
      Metastatic cancer presents a formidable clinical challenge due to the limitations of conventional therapies in addressing both primary tumors and systemic spread. Here, we developed a supramolecular nanoscale metal-organic framework platform, UIO66-IR808-POEGMA (UIP), designed to integrate multimodal imaging with potent combination therapy for systemic intervention. UIP enables simultaneous photoacoustic and fluorescence imaging, providing real-time guidance for treatment. Upon 808 nm laser irradiation, the platform mediates synergistic photodynamic and photothermal effects, leading to the effective ablation of the primary tumors. Crucially, this localized therapy induces a robust antitumor immune response. In a murine model bearing 4T1 tumors, this imaging-guided strategy completely eradicated the primary tumors and markedly suppressed the growth of distant lesions (19.8% by volume compared to the PBS group). This work demonstrates UIP as a promising integrated theranostic system for imaging-guided control of metastatic disease.
    Keywords:  against metastatic tumors; covalently engineered; immunotherapy; metal organic framework; multimodal imaging; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.1021/acsami.6c05437
  28. ACS Appl Mater Interfaces. 2026 May 27.
    Graphene Oxide Quantum Dots-Loaded Extracellular Vesicles with Inflamed Pulp-Homing Targeting Enhance Pulp Repair in Pulpitis by Upregulating Glycolysis.
    Ling Lin, Jingyan Xue, Weichun Ye, Yanrui Pan, Hui Lu, Pei Li, Dongsheng Yu, Wei Zhao.
      Preservation of vital dental pulp under inflammatory conditions remains a persistent clinical challenge in endodontics. Successful inflamed dental pulp repair in pulpitis can extend affected tooth retention, but it also imposes greater demands on the anti-inflammatory and pro-differentiation effects of therapeutic agents. This study constructed a novel drug delivery system via loading graphene oxide quantum dots (GOQDs) into extracellular vesicles (EVs) derived from inflamed dental pulp stem cells (iDPSCs) by electroporation. Upon encapsulation by iDPSC-derived EVs, these engineered EVs loaded with GOQDs (GOEs) exhibited a homologous targeting effect, as evidenced by a 2.57-fold higher internalization efficiency in iDPSCs. At 10 μg/mL, GOEs exhibited excellent biocompatibility and a proliferative effect in iDPSCs. Furthermore, GOEs regulated energy metabolism in inflamed stem cells by modulating metabolic phenotype switching via enhancing glycolysis and restoring mitochondrial function. By activating the AMPK/mTOR pathway, GOEs can coordinate the glycolysis level and NF-κB inflammatory signaling in iDPSCs, reshape the inflammatory microenvironment, and improve inflamed dental pulp repair efficacy in vitro and in vivo. This study offered a promising energy-regulating nanomaterial for clinical inflamed dental pulp repair in pulpitis, providing a valuable alternative to enhance endodontic regenerative efficacy.
    Keywords:  drug delivery; engineered extracellular vesicles; glycolysis; inflamed dental pulp repair; quantum dots
    DOI:  https://doi.org/10.1021/acsami.6c04380
  29. iScience. 2026 Jun 19. 29(6): 115960
    The Trojan Horse system composed of platelet membrane and extracellular vesicles inhibits atherosclerotic plaque progression.
    Lu Ling, Zhiwei Xue, Meilin Lv, Feiyu Mu, Mengtao Han, Zhihan Zhang, Wenchen Xing, Yanzhao Wu, Xiangjun Liang, Guohao Liu, Zhen Qin, Zhaosheng Wei, Tao Sun, Bin Huang, Peng Zhao, Jian Wang, Yaotian Hu, Xuejun Wang, Donghai Wang.
      Carotid atherosclerotic plaques are a leading cause of ischemic stroke and present a major challenge for early atherosclerosis intervention. Here we engineer a biomimetic delivery platform, such as the Trojan Horse system, composed of platelet membrane and extracellular vesicles (EVs) derived from M2-like macrophages. The resulting vesicles, called platelet-extracellular vesicles (P-EVs), selectively accumulate at injured endothelium and atherosclerotic plaques and enable the co-delivery of PIM1 siRNA and Max-40279. This strategy suppresses endothelial-mesenchymal transition, reduces macrophage foam cell formation, and attenuates inflammatory responses in lesions. In mouse models of atherosclerosis, treatment with P-EVs significantly limits plaque progression. These results establish P-EVs as a targeted approach for modulating vascular inflammation and provide a potential strategy for slowing atherosclerotic plaque development.
    Keywords:  cardiovascular medicine; drug delivery system; molecular medicine
    DOI:  https://doi.org/10.1016/j.isci.2026.115960
  30. Nanomedicine. 2026 May 27. pii: S1549-9634(26)00061-4. [Epub ahead of print] 102960
    Corrigendum to "Functional engineered mesenchymal stem cells with fibronectin‑gold composite coated catheters for vascular tissue regeneration" [Nanomed: Nanotechnol Biol Med 14 (2018) 699-711].
    Yun-Wen Chen, Shu-Chen Hsieh, Yi-Chin Yang, Shan-Hui Hsu, Mei-Lang Kung, Pei-Ying Lin, Hsien-Hsu Hsieh, Ching-Hao Lin, Cheng-Ming Tang, Huey-Shan Hung.
      
    DOI:  https://doi.org/10.1016/j.nano.2026.102960
  31. Int J Mol Sci. 2026 May 09. pii: 4212. [Epub ahead of print]27(10):
    A Comparative Analysis of iPSC, MSC, and 293T-Derived Exosomes for Parkinson's Disease Therapy.
    Kuan-Fei Chen, Syuan-Ling Lin, Chuan-Hao Kuo, Woei-Cherng Shyu, Long-Bin Jeng, Shih-Ping Liu.
      Parkinson's disease (PD) lacks effective therapeutic methods. Exosomes are specialized vesicles that feature a double-layered lipid structure and are rich in proteins, miRNA, mRNA, growth factors, and other biomolecules. Their diverse components enable tissue repair and cell activation, making exosomes a promising candidate for therapeutic applications, including for PD. Exosomes are widely studied in cancer treatment and regenerative medicine. Since these vesicles retain the characteristics of their source cells, selecting the appropriate cell type is crucial. In this study, we compared exosomes derived from induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and 293T cells in terms of particle production, protein content, cellular uptake efficiency, and therapeutic effects on PD. The results showed that exosomes derived from iPSCs outperformed those from the other two cell types in all evaluated aspects, followed by MSC-derived exosomes, while 293T-derived exosomes were the least effective. This study provides valuable comparative data to inform the selection of source cells for exosome-based therapies in regenerative medicine.
    Keywords:  Parkinson’s disease; exosome; induced pluripotent stem cell
    DOI:  https://doi.org/10.3390/ijms27104212
  32. Neural Regen Res. 2026 May 14.
    Adipocytes and macrophages after stroke: Interactions between metabolism and immunity.
    Jiaxing Xu, Shaomeng Chen, Xiaojuan Ma, Decao Yang, Jinxin Li, Baohui Xu, Qingbian Ma, Yan Wang.
      Lipid metabolism disorders and chronic inflammation are key components of stroke pathogenesis. Understanding the involvement of adipocytes and macrophages in the onset and recovery phases of stroke is crucial. This review aims to investigate the metabolic and immune interactions between adipocytes and macrophages and their roles in neural repair. Obesity and related lipid metabolism disorders drive chronic low-grade inflammation by inducing adipocyte hypertrophy, endoplasmic reticulum stress, and oxidative stress, which are the key mechanisms underlying the occurrence and repair of ischemic stroke. Hypertrophic adipocytes release free fatty acids and pro-inflammatory mediators, which recruit and polarize macrophages through the "crown-like structure," exacerbating systemic neuroinflammation and insulin resistance. Endoplasmic reticulum stress alters the secretion profile of adipocytes by activating the signaling pathways involving inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase , and activating transcription factor 6. This remodeling promotes the polarization of macrophages towards the M1 phenotype and reduces the secretion of protective hormones such as adiponectin, thereby further disrupting metabolic homeostasis. Exosomes and the miRNAs they carry serve as an important medium for communication between adipocytes and macrophages, playing a key role in the local and systemic spread of inflammation. These processes collectively lead to vascular endothelial dysfunction, disruption of the blood-brain barrier, and M1 polarization of microglia in the brain, expanding ischemic post-injury neuroinflammatory damage and hindering neural repair. Current studies have shown that targeting key enzymes in lipid metabolism, inflammatory signaling pathways, and intercellular communication carriers has potential therapeutic value. Strategies such as engineered exosomes, regulation of metabolic reprogramming, and the use of peroxisome proliferator-activated receptor γ agonists have demonstrated potential in enhancing neural repair and improving stroke outcomes in animal models. This review integrates findings from molecular research, animal models, and translational medicine to construct a conceptual framework for understanding the interaction between adipocytes and macrophages during the stroke process. Future research should integrate single-cell multi-omics and spatial transcriptomics to systematically analyze the dynamic interaction mechanisms of the fat-immune-neural axis after stroke, promoting the clinical translation of individualized metabolic immunotherapy strategies.
    Keywords:  adipocytes; endoplasmic reticulum stress; exosomes; inflammation; lipid metabolism; macrophages; nerve regeneration; obesity; stroke; therapy
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01114
  33. Iran J Basic Med Sci. 2026 ;29(4): 544-577
    Characterization of exosomes from hypoxia-activated human amniotic membrane mesenchymal stem cells.
    Hadiseh Kholgh, Fatemeh Eshghabadi, Hanieh Jafary, Kavosh Zandsalimi, Nazanin Akbari, Azadeh Soltani, Banafsheh Heidari.
       Objectives: Hypoxia is a physical stimulus that enhances stem cell activities to produce more cellular derivatives, particularly exosomes. Enhancing the quantity and quality of exosomes can improve their therapeutic properties. The study aimed to evaluate the effects of normoxic (22%O2) and hypoxic (1%O2) conditions on the characteristics of amniotic membrane-derived mesenchymal stem cells (AM-MSCs) and their exosomes.
    Materials and Methods: AM-MSCs were isolated, confirmed, and cultured under normoxic and hypoxic conditions. Exosomes were extracted from AM-MSCs and assessed for morphological characteristics (size/distribution/surface topography), structural properties (aggregation/colloidal particle behavior/surface charge/stability), chemical features (functional groups/ionic interactions), biological capacities (total protein concentration), and biocompatibility (microbiological quality/cytotoxicity/irritation/sensitization).
    Results: Hypoxia did not adversely affect the stemness potential of AM-MSCs (P>0.05). The average sizes of exosomes derived from AM-MSCs (AM-MSCs-Exo) were 185.7±23 nm (PI=0.756) and 145.4±36 nm (PI=0.420) under normoxic and hypoxic conditions, respectively (P≤0.05). Zeta potential of AM-MSCs-Exo was -12.57±0.5 mV under normoxia, while it was -2.37±0.73 mV in the hypoxic conditions. Exosomes from hypoxia-treated cells exhibited greater uniformity, dispersion, and stability than those from the normoxic group, resulting in reduced fluctuation under scattered light over time (P≤0.05). The total protein concentration in the hypoxic group was significantly higher than in the normoxic conditions (5.003 mg/ml vs. 4.109 mg/ml, representing a 1.22-fold increase) (P≤0.01). Exosomes extracted under normoxic and hypoxic conditions demonstrated acceptable biocompatibility with no signs of cytotoxicity, irritation, sensitivity, or microbial contamination.
    Conclusion: Hypoxic preconditioning enhances the yield and physicochemical stability of AM-MSC-derived exosomes, due to their unique composition and functional properties.
    Keywords:  Amniotic membrane; Biocompatibility; Exosomes; Extracellular vesicles; Hypoxia; Mesenchymal stem cells
    DOI:  https://doi.org/10.22038/ijbms.2026.90923.19618
  34. Vaccines (Basel). 2026 May 15. pii: 440. [Epub ahead of print]14(5):
    Bacterial Membrane Vesicles as Versatile Platforms for Systemic and Mucosal Vaccines.
    Si Hyun Park, Young Min Son.
      Bacterial membrane vesicles (BMVs), encompassing outer membrane vesicles (OMVs) released from Gram-negative bacteria and extracellular vesicles (EVs) released from Gram-positive bacteria, have emerged as promising vaccine platforms owing to their intrinsic immunostimulatory properties and capacity to deliver a wide range of antigens. Although conventional vaccines effectively prevent infectious diseases, their long-term efficacy is often limited by antigenic variation and reliance on a restricted number of licensed adjuvants. BMVs, as self-adjuvanting systems, enable both antigen delivery and innate immune activation. BMVs are nanoscale lipid bilayer structures enriched with pathogen-associated molecular patterns (PAMPs), facilitating their recognition and uptake by antigen-presenting cells. This leads to the activation of pattern recognition receptors and the induction of pro-inflammatory cytokines, type I interferons, and adaptive immune responses, including antibody production and Th1- and Th17-biased cellular immunity. Recent studies highlight the versatility of BMVs as vaccine platforms across bacterial, fungal, and viral infection models. BMVs induce protective immunity by promoting both systemic and mucosal immune responses, thereby reducing bacterial burden and limiting pathogen colonization across diverse infection models. These properties have supported their application in viral vaccine development, including influenza and SARS-CoV-2, with the potential to enhance mucosal immunity. Despite these advantages, challenges remain in standardization, safety, and antigen-loading efficiency. Engineered BMVs incorporating protein or mRNA antigens may further enhance antigen presentation and CD8+ T cell responses. This review summarizes the biological features, immunological mechanisms, and future potential of BMVs in vaccine development.
    Keywords:  bacterial membrane vesicles; mucosal immunity; self-adjuvanting system; systemic immunity; vaccine platform
    DOI:  https://doi.org/10.3390/vaccines14050440
  35. Tissue Eng Part B Rev. 2026 May 23. 19373368261450049
    Gelatin Methacryloyl Hydrogels as a Multifaceted Platform for Promoting Nerve Regeneration.
    Shuaiwu Chen, Yuqi Cao, Yuanbo Wang, Chenggang Liu.
      Nerve injuries pose a significant clinical challenge in both the central and peripheral nervous systems, which often lead to permanent functional deficits. Nerve tissue engineering offers a promising path forward, and gelatin methacryloyl (GelMA) hydrogels have emerged as a powerful and versatile platform in this endeavor. Derived from natural collagen, GelMA possesses inherent biocompatibility and cell-adhesive properties, while its photocrosslinkable nature allows for the precise tuning of its mechanical stiffness, degradation rate, and porous architecture to recapitulate the native neural microenvironment. This review comprehensively elucidates the evolution of GelMA from a passive physical support to an active and instructive biomaterial. We explore a wide array of functionalization strategies, including the incorporation of therapeutic cells, the sustained delivery of neurotrophic factors, and the integration of conductive materials to guide regeneration. Furthermore, we discuss the development of advanced stimuli-responsive systems and the application of 3D bioprinting to fabricate anatomically complex nerve guidance conduits. Ultimately, this work establishes GelMA as a pivotal technology for developing the next generation of intelligent and clinically translatable strategies for nerve repair.Impact StatementThis review highlights the transformative potential of gelatin methacryloyl (GelMA) hydrogels in nerve tissue engineering. By comprehensively analyzing advanced functionalization strategies and "smart" stimuli-responsive systems that adapt to pathological microenvironments, this work underscores the capacity of GelMA to overcome critical barriers in neural repair. We detail how these versatile scaffolds can be engineered for precise drug delivery, electrical conductivity, and gene editing. These insights provide a roadmap for developing next-generation, autonomous biomaterials, paving the way for personalized clinical solutions that significantly enhance functional recovery in patients with severe neuronal injuries.
    Keywords:  3D bioprinting; gelatin methacryloyl; nerve injuries; nerve tissue engineering; regeneration
    DOI:  https://doi.org/10.1177/19373368261450049
  36. Discov Nano. 2026 May 27. pii: 220. [Epub ahead of print]21(1):
    Exosome-loaded nanoradiosensitizers in radiotherapy for preventing post-irradiation tumor recurrence: mechanisms, preclinical evidence, and translational challenges.
    Daniel Ejim Uti, Josephine E Egbung, Bassey Omeh Anthony, Ogar Rose Omari, Wilson Achu Omang, Waheeb Sami Aggad, Hailah M Almohaimeed, Neeraj Bainsal, Sandeep Kumar Shukla, Kranti Kiran Reddy Ealla, Esther Ugo Alum.
      Radiotherapy remains a cornerstone in cancer treatment, yet its therapeutic efficacy is often limited by radioresistance, tumor heterogeneity, and recurrence post-irradiation. Nanotechnology has emerged as a promising avenue to enhance radiosensitization, improve tumor selectivity, and reduce off-target toxicity. Among these, exosome-loaded nanoradiosensitizers represent an innovative strategy, leveraging the natural biocompatibility, tumor-homing ability, and immunomodulatory properties of exosomes to deliver radiosensitizing agents with precision. This review examines the design principles, fabrication strategies, and functional mechanisms of exosome-based nanoradiosensitizers, highlighting how they enhance DNA damage, modulate the tumor microenvironment, and overcome intrinsic and acquired radioresistance. We discuss the molecular mechanisms underlying radiosensitization, including reactive oxygen species (ROS) amplification, cell-cycle modulation, hypoxia alleviation, and immune system engagement. Furthermore, we explore in vitro and in vivo preclinical evidence demonstrating the efficacy of these systems in reducing tumor recurrence post-irradiation. Challenges such as scalable exosome production, cargo loading efficiency, targeted delivery, and regulatory considerations are critically evaluated. Finally, the review outlines translational perspectives, potential combinatorial therapies, and key considerations for clinical trial design. By integrating insights from nanomedicine, radiobiology, and exosome biology, this review aims to provide a comprehensive framework for the development of next-generation exosome-based nanoradiosensitizers, ultimately enhancing radiotherapy outcomes and minimizing tumor relapse in resistant cancers.
    Keywords:  Exosome-based nanocarriers; Radiosensitization; Radiotherapy enhancement; Tumor microenvironment; Tumor recurrence
    DOI:  https://doi.org/10.1186/s11671-026-04681-9
  37. Life Sci. 2026 May 22. pii: S0024-3205(26)00284-5. [Epub ahead of print]400 124475
    Extracellular vesicles for diabetes and its complications: Harnessing mammalian and plant sources from direct interventions to engineered applications.
    Tian Li, Yu Lu, Jianbo Wu, Gaoping Zhao, Yong Xu.
      Current therapies for diabetes mellitus, a highly prevalent chronic metabolic disorder, rarely achieve etiological intervention and are limited by poor patient compliance and significant side effects. Extracellular vesicles (EVs), nanoscale carriers of intercellular communication, offer a promising therapeutic alternative due to their high biocompatibility, low immunogenicity, and inherent capacity for delivering biomolecules to specific targets. This review systematically synthesizes recent progress in EV-based strategies for diabetes. First, we examine how mammalian-derived EVs (such as from mesenchymal stem cells and immune cells) directly protect and restore pancreatic β-cells, restore immune tolerance, and ameliorate systemic insulin resistance. Second, we highlight the emerging potential of plant-derived EVs, which allow for oral administration and modulate metabolism via gut-organ axes. We further discuss the engineering of EVs into targeted drug delivery systems, with a focus on breakthroughs in oral insulin delivery and their applications in treating diabetic complications, including nephropathy, chronic wounds, and liver-brain axis-related disorders. Finally, we outline the key challenges of standardization, scalable production, and clinical translation, proposing a roadmap for future research. This comprehensive analysis underscores the potential of EVs to provide transformative strategies for diabetes management through multifaceted mechanisms and innovative engineering strategies.
    Keywords:  Diabetes mellitus; Drug delivery; Engineering modification; Extracellular vesicles
    DOI:  https://doi.org/10.1016/j.lfs.2026.124475
  38. Regen Biomater. 2026 ;13 rbag032
    Biomimetic lung-targeting vehicle coupled with cryo-shocked leukocyte and inflammation-anchored liposome for drug delivery and anti-inflammation in treatment of acute pneumonia.
    Jinniu Zhang, Yixing Zeng, Yun Huang, Chunyun Zhu, Wenhao Shen, Yingjing Miao, Nianping Feng, Tianyuan Ci.
      Acute pneumonia is a severe pulmonary inflammation, and it is critical to promptly suppress the dysregulated inflammatory responses to prevent mortality. Glucocorticoids are the first-line therapeutic drugs but with poor tissue selectivity and dose-dependent adverse effects. In this work, cryo-leukocyte, an autologous cell-derived immunosuppressor, was created by leveraging the cryo-shocking technology by the quick shock of normal leukocytes with liquid nitrogen. After coupling with aICAM-1 functionalized liposomes, this micro/nano composite system could achieve efficient and prompt inflammation alleviation in acute pneumonia. The engineered cryo-leukocytes were of well biocompatibility after evaluation of blood toxicity, tissue toxicity, acute toxicity and long-term biosafety for over 6 months, etc. Cryo-leukocytes preserved similar cellular receptors as normal leukocytes, capable of recognizing and binding inflammatory cytokines but without activation of immune cascade, thus exhibiting obvious anti-inflammation efficacy by acting as 'mixed cytokines antibodies'. The immunosuppression efficacy of cryo-leukocytes was also superior than that of its sub-group cells of cryo-neutrophil, cryo-monocyte and cryo-lymphocyte, due to relative wide protein expressions that are related to the immune responses. Besides, cryo-leukocytes coupled with aICAM-1 functionalized liposome exhibited obvious anchoring effect in inflammation sites by the interaction of ICAM-1 antibody and ICAM-1 molecules that were over-expressed on inflammatory pulmonary endothelial cells, thus served as superior drug lung-targeting vehicle to maximally enhance the accumulation of traditional Chinese and Western medicines in the lungs. A total of 68.1% of drug signals could be observed in lung tissues compared with other major organs after intravenous injection, significantly higher than that of micro-sized drug-loaded cryo-leukocyte (18.6%) and nano-sized drug-loaded aICAM-1-liposome (12.2%). In a lipopolysaccharide-induced acute pneumonia mice model, the drug-loaded cryo-leukocyte achieved superior anti-inflammation efficacy with 87.5% survival of mice after treatment.
    Keywords:  cryo-shocking; inflammation targeting; leukocytes; pneumonia; targeting drug delivery
    DOI:  https://doi.org/10.1093/rb/rbag032
  39. J Transl Med. 2026 May 29.
    Engineering RVG-modified exosomes for targeting TGF-β1 signaling in stroke recovery.
    Wang Zhao, Lei Hao, Jiangwei Zhang, Jun Zhu, Jia Kuang, Meibiao Zhang, Yonggang Zhang, Xiaoxing Xiong, Zhao Yang.
       OBJECTIVE: To investigate the role of TGF-β1 signaling in astrocyte-neuron interactions after ischemic stroke and to develop a brain-targeted engineered exosome system, EXO-RVG-SD208, for promoting neural repair.
    METHODS: Public datasets and transcriptomic analyses were used to characterize the dynamic changes of TGF-β1 after stroke, and key targets were identified through GO, KEGG, and WGCNA analyses. A brain-targeted engineered exosome, EXO-RVG-SD208, was constructed and characterized for its physicochemical properties. Its inhibitory effect on the TGF-β1/Smad2/3 pathway in astrocytes and its neuroregenerative potential were evaluated in oxygen-glucose deprivation/reoxygenation (OGD/R) and neuron-astrocyte co-culture models. Therapeutic efficacy was further assessed in a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model. Integrated multi-omics analyses were performed to explore the downstream mechanisms involved in neural repair.
    RESULTS: TGF-β1 was markedly upregulated after stroke and was predominantly derived from astrocytes, where it was closely associated with neuroinflammation and impaired neuroplasticity. EXO-RVG-SD208 effectively inhibited activation of the TGF-β1/Smad2/3 pathway, promoted astrocyte phenotypic remodeling, enhanced neuronal synaptic activity, and improved functional recovery in MCAO/R mice. Multi-omics analyses further indicated that the therapeutic effects were associated with the regulation of mTOR, BDNF, and MAPK-related pathways.
    CONCLUSION: EXO-RVG-SD208 effectively delivered TGF-β1 inhibitor to the brain, suppressed astrocytic TGF-β1/Smad2/3 activation, facilitated astrocyte-neuron remodeling, synaptic reconstruction, and neural functional recovery, presenting a promising nanodelivery strategy for stroke rehabilitation.
    Keywords:  Astrocytes; Exosomes; Integrated multi-omics; Ischemic stroke; Synaptic reconstruction; TGF-β1
    DOI:  https://doi.org/10.1186/s12967-026-08271-2
  40. J Nanobiotechnology. 2026 May 24.
    Macrophage exosome-modified Mn/Se nanoheterostructure induces post-infarction cardiomyocyte regeneration and immunometabolic microenvironment repair.
    Linghuan Guo, Zhi Xiong, Kai Sheng, Qiang Zhang, Jiahui Cheng, Lingling Xu, Wen Wang, Guoyang Zhang, Tingting Yao, Dan Wang, Xiaoer Wei, Mingkang Wang, Yang Lyu, Xinxin Zhao, Lixian Jiang, Xiaojun Cai, Yuanyi Zheng, Lidan Liu, Yan Zhou, Bo Li, Yuehua Li.
      Myocardial infarction (MI) is the most lethal cardiovascular disease and poses a critical threat to global health. While current MI therapies partially improve cardiac function, advanced precision therapies with translational potential capable of interrupting the vicious pathological cycles remain a pivotal challenge to be addressed. Here, based on a Mn/Se nanoheterostructure that meets human elemental requirements, we constructed a PMS@ME nanotherapeutic system for achieving efficient post-MI repair. Polydopamine was incorporated to synergistically enhance biocompatibility and therapeutic efficacy. The surface is modified with exosomes derived from macrophages that highly express adhesion receptors, enabling precise targeting to the myocardial injury area. PMS@ME administration promotes cardiomyocyte survival, extracellular repair, and mitochondrial homeostasis, while suppressing oxidative damage and immune-inflammatory disorders, achieving preserved cardiac function. Importantly, PMS@ME can induce cardiomyocyte to restart the cell cycle and promotes post-MI cardiomyocyte regeneration by inhibiting the Hippo signaling pathway. These findings demonstrate the potential of the PMS@ME system in MI treatment, offering a blueprint for designing multifunctional nanotherapies tailored to human elemental essentials.
    Keywords:  Cardiomyocyte proliferation; Immune and metabolic microenvironment; Macrophage-derived exosome; Mn/Se nanoheterostructure; Myocardial infarction
    DOI:  https://doi.org/10.1186/s12951-026-04572-2
  41. Biomater Sci. 2026 May 26.
    Hydrogel-exosome synergistic system: mechanisms, applications and future prospects in regenerative medicine.
    Bin Xie, Yuyi Kang, Shuihao Zhao, Zhiyun Wu, Zelin Wu, Xiubin Kuang, Jiahong Jiang, Nuo Xu, Xudong Lin, Jun Wu, Tak-Man Wong, Shaoquan Bian, Xiaoli Zhao, Zhengqiang Yuan.
      Hydrogels and exosomes are complementary and thus can be combined for regenerative medicine and emerging therapies. This strategy leverages the advantages of hydrogels to enhance the therapeutic potential of exosomes. Hydrogels offer numerous therapeutic and regenerative advantages, such as tailorable mechanical properties, a supportive extracellular matrix-like microenvironment, superior biocompatibility, rapid responses to environmental stimuli, and the ability to encapsulate and control the release of therapeutic agents. These attributes can be utilized to enable the long-acting delivery of exosomes. Exosomes, small extracellular vesicles (30-150 nm) secreted by cells, carry bioactive molecules such as proteins, lipids, and nucleic acids, mediating intercellular communication and modulating cellular behaviors. The integration of hydrogels and exosomes represents a potential approach in regenerative medicine, leveraging their synergistic properties to enhance tissue repair and regeneration. This combination has been reported to enhance wound healing, promote cartilage repair, and ameliorate neuronal injury. Recent advancements include the development of smart hydrogels that respond to environmental stimuli (e.g., pH, temperature) to control exosome release, optimizing the therapeutic efficacy. Additionally, exosome engineering for enhanced cargo loading and targeting capabilities further advances precision regenerative medicine. This review explores the latest progress, challenges, and future directions in harnessing hydrogels and exosomes for recently developed regenerative medicine and therapeutic applications.
    DOI:  https://doi.org/10.1039/d6bm00274a
  42. Cancer Lett. 2026 May 24. pii: S0304-3835(26)00380-0. [Epub ahead of print] 218617
    Exosome mediated crosstalk in gastrointestinal cancers progression: special focus on Integrin β3 as a cargo.
    Ganji Purnachandra Nagaraju, Sujith Sarvesh, Bassel F El-Rayes.
      Intercellular communication within the tumor microenvironment (TME) is highly active in gastrointestinal (GI) cancers, and exosomes have an important function in tumor development, progression, metastasis, angiogenesis, and drug resistance. Exosomes secreted by tumor cells actively remodel their local environment by delivering oncogenic proteins, genetic material, and integrins, contributing to processes such as invasion, immune escape, and metastatic niche formation. Cancer-associated fibroblasts (CAFs) are a main source of exosomes in the stroma, and their presence boosts tumor progression by orchestrating changes in the extracellular matrix composition, metabolism, and epithelial to mesenchymal transition. Similarly, exosomes produced by endothelial cells facilitate angiogenesis and increase vascular permeability, providing a mechanism for tumor spread. One of the key factors recently discovered in exosomes is the integrin β3, which plays a major role in organotropic metastasis, cell adhesion, migration, and activation of signaling pathways in GI cancers. In this review, the biological roles of exosomes isolated from tumors, CAFs, and endothelial cells have been highlighted, especially with reference to the functional significance of integrin β3 in GI cancers. This review also provides insight into the application of integrin β3 in exosomes as a biomarker for early detection, diagnosis, and treatment. The knowledge gained through exosome-based signaling could lead to new approaches for interfering with TME-associated tumor progression.
    Keywords:  Exosomes; gastrointestinal cancers; immune suppression; integrin β3; reprogramming; tumor progression
    DOI:  https://doi.org/10.1016/j.canlet.2026.218617
  43. J Pept Sci. 2026 Jul;32(7): e70105
    Structure-Guided Engineering of Histidine-Rich pH-Switchable Endosomolytic Peptides for Spleen-Selective siRNA Delivery to Inflammatory Macrophages.
    Dilpreet Singh.
      Extrahepatic delivery of small interfering RNA (siRNA) remains a major translational challenge because most nanocarriers preferentially accumulate in the liver, while endosomal sequestration limits productive cytosolic release. Inflammatory macrophages in the spleen are attractive therapeutic targets in systemic inflammation, yet spleen-selective delivery systems with efficient endosomal escape remain underdeveloped. Here, a structure-guided peptide engineering workflow was used to generate histidine-rich, pH-switchable endosomolytic peptides for spleen-selective siRNA delivery. Sequence design integrated pH-dependent charge transition modeling, amphipathic helix prediction, membrane interaction scoring, and safety filtering. Six candidate peptides were synthesized and evaluated for pH-responsive structure, membrane disruption, hemocompatibility, siRNA complexation, serum stability, macrophage uptake, endosomal escape, biodistribution, and anti-inflammatory efficacy. The lead peptide, HSEP-6, showed a predicted net charge increase from +3.1 at pH 7.4 to +7.4 at pH 5.5, helix content increasing from 17% to 56%, and acidic calcein release increasing from 9% to 62%. In inflammatory macrophages and LPS-challenged mice, HSEP-6 enabled efficient siRNA delivery, spleen-selective accumulation, marked Irf5 silencing, reduced TNF-α and IL-6, and no measurable systemic toxicity, supporting histidine-rich pH-switchable peptides as a rational platform for extrahepatic RNA delivery.
    Keywords:  Irf5 silencing; endosomal escape; extrahepatic nanomedicine; histidine‐rich peptides; inflammatory macrophages; pH‐switchable peptides; siRNA; spleen‐selective delivery
    DOI:  https://doi.org/10.1002/psc.70105
  44. Arch Soc Esp Oftalmol (Engl Ed). 2026 May 25. pii: S2173-5794(26)00140-4. [Epub ahead of print] 502600
    Use of Exosomes as Adjuvant Therapy in the Reconstruction of Traumatic Eyelid Wounds: A Case Report.
    A Velasco Y Levy.
      Traumatic eyelid wounds with tissue loss pose a reconstructive challenge due to the risk of inflammation-driven fibrosis and functional impairment. Mesenchymal stem cell-derived exosomes have demonstrated regenerative and antifibrotic effects in cutaneous wound-healing models. We report a case of high-energy periocular trauma in which standard oculoplastic reconstruction was supplemented with staged topical and microneedling-assisted exosome therapy. Accelerated epithelialization, favorable scar modulation, and preservation of eyelid contour and function were observed without adverse events. This case supports the feasibility of exosome-based therapy as an adjunct in complex eyelid wound reconstruction.
    Keywords:  Exosomas; Exosomes; Eyelid Reconstruction; Medicina Regenerativa; Oculoplastic Surgery; Oculoplástica; Periocular Trauma; Reconstrucción Palpebral; Regenerative Medicine; Reparación de Heridas Palpebrales; Trauma Periocular; Wound Healing
    DOI:  https://doi.org/10.1016/j.oftale.2026.502600
  45. J Funct Biomater. 2026 May 19. pii: 252. [Epub ahead of print]17(5):
    Recombinant Spider Silk Enhances Engineered Cartilage Formation.
    Hongji Zhang, Xinyu Huang, Jinwen Zhang, Fengjie Zhang, Fei Sun, Chao Wan.
      Articular cartilage is characterized by its avascular, aneural, and alymphatic nature, which confers a limited intrinsic capacity for self-repair. Current regenerative strategies primarily focus on alleviating pain, mitigating symptoms, and restoring joint function. However, their long-term efficacy remains uncertain. Cartilage tissue engineering has emerged as a promising alternative to conventional therapies, offering innovative solutions for articular cartilage regeneration. Central to this approach is the development of functional biomaterials capable of supporting chondrogenic cell adhesion, proliferation, and differentiation, thereby facilitating effective cartilage repair. In this study, we introduce a novel protein-based recombinant spider silk (RSS) as a potential biomaterial for modulating chondrocyte behavior and enabling engineered cartilage formation both in vitro and in vivo. RSS was generated through molecular cloning and processed into silk fibers using biomimetic spinning and acidic coagulation techniques. In micromass cultures of murine chondrocytes, RSS significantly promoted cell aggregation, resulting in increased cell density. Alcian blue and Oil Red O staining demonstrated that RSS-treated cultures produced abundant glycosaminoglycans, a hallmark of chondrogenic activity, while exhibiting minimal lipid accumulation. These findings suggest that RSS supports chondrogenic differentiation and suppresses adipogenic lineage commitment. Real-time PCR analysis revealed upregulation of the chondrogenesis-related gene Sox9 and downregulation of the adipogenic marker PPARγ and the hypertrophic marker Runx2 in RSS-treated micromass cultures. RNA sequencing further corroborated these observations, underscoring the role of RSS in modulating extracellular matrix (ECM) remodeling in chondrocytes. In a subcutaneous transplantation model using severe combined immunodeficiency (SCID) mice, chondrocytes encapsulated in three-dimensional hydrogel scaffolds containing RSS exhibited significantly enhanced ECM accumulation compared to RSS-free controls, indicating that RSS supports the maintenance of the chondrocyte phenotype and promotes cartilage formation in vivo, and underscoring its promising potential as a component of hydrogel composite systems. These findings highlight the potential of RSS as a functional biomaterial to preserve chondrocyte functionality and advance engineered cartilage formation, presenting a promising avenue for cartilage tissue engineering and regeneration.
    Keywords:  biomaterials; cartilage tissue engineering; hydrogel composite; protein hydrogel; recombinant spider silk (RSS)
    DOI:  https://doi.org/10.3390/jfb17050252
  46. Cancer Lett. 2026 May 24. pii: S0304-3835(26)00381-2. [Epub ahead of print]654 218618
    Desmoplasia and therapeutic resistance in pancreatic ductal adenocarcinoma.
    Yashwardhan Ghanwatkar, Raghu Ramanathan, Ram I Mahato.
      Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal solid malignancies, and its therapeutic failure reflects both aggressive tumor-cell biology and the highly restrictive tumor microenvironment (TME). A defining hallmark of PDAC is desmoplasia, an extensive, extracellular matrix (ECM)-rich fibroinflammatory reaction that frequently exceeds the tumor cell compartment itself. Evidence from genetically engineered mouse models and human specimens identifies pancreatic stellate cells (PSCs) as the dominant architects of this stroma. Upon activation, PSCs differentiate into matrix-producing fibroblasts that drive collagen and hyaluronan (HA) accumulation, tissue stiffening, and vascular compression. ECM remodeling elevates interstitial pressure, collapses perfused vessels, and establishes profound hypoxia, which in turn reinforces fibroblast activation and matrix deposition through feed-forward signaling loops. These hypoxic, high-stress conditions severely restrict the delivery of cytotoxic agents, biologics, and nanomedicines, while simultaneously activating mechanotransduction pathways that enhance tumor cell survival under therapy. Clinical attempts to ablate stromal components validated the barrier function of desmoplasia but also revealed its tumor-restraining roles, exposing the limitations of indiscriminate depletion. This review synthesizes PSC-driven stromal initiation, matrix biomechanics, spatial zonation, and formulation-aware delivery into a single framework to explain why stromal targeting has repeatedly failed clinically and which normalization strategies are most likely to improve therapeutically effective exposure in PDAC.
    Keywords:  Desmoplasia; Drug delivery; Hypoxia; Pancreatic ductal adenocarcinoma; Stromal remodeling; Therapeutic resistance
    DOI:  https://doi.org/10.1016/j.canlet.2026.218618
  47. Biosens Bioelectron. 2026 May 25. pii: S0956-5663(26)00486-0. [Epub ahead of print]310 118854
    Digital droplet microfluidics integrating DNA walkers and CRISPR-Cas13a for simultaneous surface protein and miRNA profiling in single exosomes.
    Shu Xiao, Jialei Song, Haitian Chen, Wen Yin, Xijing Yan, Kunpeng Hu, Jingyu Shi, Mo Yang.
      Tumor-derived exosomes carry multi-scale molecular signatures (e.g., surface proteins and nucleic acids) that reflect tumor heterogeneity, yet simultaneously profiling these biomarkers in single intact vesicles remains technically challenging. Herein, we developed a digital droplet microfluidic platform that integrates a DNA walker and a CRISPR/Cas13a system for the simultaneous detection of surface proteins (EpCAM, HER2) and miRNA (miR-21) at the single exosome level. This platform employed engineered liposome nanoprobes (eLipo-NPs) with EpCAM aptamers and hairpin probes (HPs) functionalized on their outer membranes, and encapsulated a CRISPR/Cas13a system within their lumen. Upon co-encapsulation with single exosomes into droplets, EpCAM-mediated membrane fusion redistributed HPs across the hybrid membrane and delivered CRISPR/Cas13a into the exosomes. The membrane-anchored DNA walker then bound HER2 and drove cyclic DNAzyme cleavage of HPs to restore red fluorescence. At the same time, crRNA-guided Cas13a recognized miR-21 and triggered trans-cleavage of reporters to generate green fluorescence. Digital counting of dual-positive droplets enabled quantitative single-exosome analysis with a limit of detection (LOD) of 10 particles/μL and a detection time of 60 min. Clinical validation using plasma-derived exosomes from 24 breast cancer patients and 14 healthy donors demonstrated distinct distributions among HER2-positive, HER2-negative, and healthy control groups, with the percentage of dual-positive droplets significantly correlated with clinical HER2 status, highlighting the platform's potential for liquid biopsy and precision oncology.
    Keywords:  CRISPR-Cas13a; Cancer diagnostics; DNA walker; Droplet-based microfluidics; Single exosomes
    DOI:  https://doi.org/10.1016/j.bios.2026.118854
  48. Adv Sci (Weinh). 2026 May 25. e24231
    Endogenous Engineering Reprograms Extracellular Vesicles for Enhanced Therapeutic Function.
    Jinghui Wang, Wenxuan Zhao, Xiaoming Hu, Yishu Wang, Peidong Yang, Diwei Zheng, Yugang Wang, Guanghui Ma, Min Shi, Wei Wei, Shuang Wang.
      Extracellular vesicles (EVs) have emerged as versatile biological carriers capable of transporting diverse therapeutic cargos. Their endogenous biogenesis pathways provide unique opportunities to regulate cargo selection through both environmental modulation and genetic programming. This review outlines how EV-producing cells can be reprogrammed to load functional proteins and nucleic acids by combining environmental cues with genetic modifications that leverage intrinsic sorting machinery and engineered molecular interactions. For protein cargo, we outline strategies that reshape EV composition through physiological stimuli, as well as genetically encoded systems designed to recruit proteins via scaffold fusion, peptide tags, or fusion-independent mechanisms. For nucleic acid cargo, we highlight approaches that leverage environment-driven alterations in RNA abundance, together with targeted loading methods that rely on scaffold-RNA-binding proteins (RBPs) fusion constructs, natural sorting motifs, and sorting-related RBPs to enrich miRNAs, mRNAs, and ribonucleoprotein complexes. We further summarize recent therapeutic applications of these endogenous engineering strategies in cardiovascular, hepatic, neurological diseases, and cancer. Finally, we discuss future directions, including high-throughput discovery of sorting elements, scalable biomanufacturing, and improved standardization, which together will advance the development of programmable and clinically translatable EVs-based therapeutics.
    Keywords:  endogenous engineering; extracellular vesicles; nucleic acid; protein cargo; therapeutic applications
    DOI:  https://doi.org/10.1002/advs.202524231
  49. Microb Drug Resist. 2026 May 25. 10766294261441705
    Endolysins, Depolymerases, Holins, and VALs: Phage-Derived Proteins for Combating Antimicrobial Resistance.
    Zahra Nasiri Shoeibi, Farzaneh Rafiee, Sousan Akrami, Zahra Ghandehari, Mohammad Mehdi Feizabadi.
      The global rise of multidrug-resistant (MDR) bacteria has renewed interest in bacteriophage-derived enzymes as alternative antibacterials. Phage-encoded lytic proteins-including holins, endolysins, polysaccharide depolymerases, and virion-associated lysins (VALs)-act via distinct mechanisms to disrupt bacterial cells or their protective polysaccharide barriers. Holins accumulate in the bacterial membrane and suddenly form pores, enabling endolysins to access and cleave peptidoglycan bonds. Endolysins are peptidoglycan hydrolases (glycosidases, amidases, endopeptidases, etc.) that cause rapid osmotic lysis of Gram-positive pathogens and, if engineered (e.g., fused to membrane-penetrating peptides), can kill Gram-negative bacteria from without. Polysaccharide depolymerases degrade bacterial capsules, biofilm exopolysaccharides and LPS O-antigens, stripping away virulence factors and exposing underlying cells to phage or host defenses. VALs (or VAPGHs) are phage tail enzymes that locally cleave peptidoglycan at infection onset to permit viral DNA entry. Each class has been studied in natural and engineered forms (e.g., "artilysins" and "chimeolysins" with optimized activity or spectrum). These proteins exhibit rapid, specific bacteriolysis (often synergistic with antibiotics) and low resistance propensity, but challenges remain in delivery, stability, and immunogenicity. Here, we review the molecular actions, advantages and limitations, and the therapeutic applications of holins, endolysins, depolymerases, and VALs (natural and engineered) against MDR infections.
    Keywords:  antimicrobial resistance; depolymerases; endolysins; holins; phage-derived enzymes; virion-associated lysins (VALs)
    DOI:  https://doi.org/10.1177/10766294261441705
  50. J Hazard Mater. 2026 May 22. pii: S0304-3894(26)01481-0. [Epub ahead of print]513 142503
    Synergistic engineering of a GRAS-certified strain: Transforming Bacillus subtilis 168 into a high-performance nicotine scavenger.
    Dan Li, Xinyu Qi, Zeying Zhang, Xiaofei Mou, Yong Meng, Chunxian Yang, Lingjiang Zeng, Xiaoqiang Liu, Fangyuan Zhang, Xiaozhong Lan, Min Chen, Sheng Tong, Zhihua Liao.
      Nicotine poses a significant threat to human health owing to its complex environmental exposure. Microbial detoxification presents a promising strategy for environmental remediation and in vivo intervention, but its application is limited by the scarcity of safe platforms, a challenge rooted in the trade-off between heterologous enzyme activity and host fitness. Here, we engineered the GRAS-certified Bacillus subtilis 168 into a nicotine-scavenging probiotic strain by introducing two FAD-dependent enzymes, nicotine oxidoreductase variant (NicA2v) and pseudooxynicotine amine oxidase (Pnao), which sequentially convert nicotine into 3-succinoylsemialdehyde-pyridine (SAP) by cleaving the toxic methylamine group. To overcome this limitation, we adopted a differentiated regulatory strategy: for NicA2v, balanced and sustained expression was achieved using a moderately strong promoter (P43); for Pnao, conventional temperature and transcriptional regulation proved ineffective due to its narrow functional window. We therefore developed a novel upstream open reading frame (uORF)-based translational attenuator that modulates protein output without altering transcription. This enabled functional expression of a high-activity Pnao homolog (Pppnao-S16) from Pseudomonas putida S16, which was further optimized via protein engineering to generate the enhanced variant Pppnao-S16-R54Q. The final strain, engineered via CRISPR-Cas9-mediated genome integration of dual P43-NicA2v copies and one uORF-mediated Pppnao-S16-R54Q cassette, efficiently degraded 20 μM nicotine to SAP within 24 h. Furthermore, this strain demonstrated strong tolerance to 2.5 mM nicotine, underscoring its potential to reduce health risks associated with nicotine exposure. Hence, this work delivers a safe, high-performance probiotic chassis for nicotine detoxification and provides a novel perspective for constructing microbial platforms against other hazardous xenobiotics.
    Keywords:  B. subtilis 168; Engineering; Nicotine detoxification; Nicotine oxidoreductase (NicA2); P(43) Promoter; Pseudooxynicotine amine oxidase (Pnao); Translational reinitiation
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.142503
  51. Cancer Cell Int. 2026 May 25. pii: 197. [Epub ahead of print]26(1):
    Cracking the shield: oncolytic viruses versus the tumor-immune fortress.
    Azza M El-Derby, Nouran T Salem, Noha Hesham, Tamer Z Salem.
      Oncolytic viruses (OVs) have emerged as a promising cancer therapy due to their natural selectivity to replicate in and destroy cancer cells. However, despite encouraging preclinical and early clinical outcomes, the therapeutic efficacy of OVs in solid tumors remains limited. Recently, OVs have been genetically modified to enhance tumor specificity, promote antitumor immune activation, and overcome barriers imposed by the tumor microenvironment (TME). Hepatocellular carcinoma presents a uniquely challenging solid tumor microenvironment for oncolytic virotherapy, characterized by dense fibrotic stroma, potent hepatic immune clearance, and immunosuppressive signaling that collectively limit viral delivery, intratumoral spread, and therapeutic efficacy. The review provides an updated overview of clinical and preclinical studies of naturally occurring and engineered OVs, with a particular focus on the biological and translational challenges that restrict their effectiveness in HCC. In addition, it highlights the strategies developed to overcome delivery barriers, immune clearance, and tumor heterogeneity, which represent key obstacles to durable therapeutic responses. Strategies such as stromal targeting, hypoxia-adapted constructs, and the use of 3D organoid models as mimic platforms to evaluate delivery and therapeutic strategies are also discussed. Finally, this review aims to integrate recent advances in viral engineering, immune modulation, and organoid models, and critically evaluates how these approaches, together with emerging clinical trial data, can inform the rational design of next-generation oncolytic viruses.
    Keywords:  Hepatocellular Carcinoma (HCC); Immunotherapy; Oncolytic Viruses (OVs); Tumor Microenvironment (TME); Viral engineering
    DOI:  https://doi.org/10.1186/s12935-026-04331-1
  52. Pharmaceutics. 2026 Apr 27. pii: 534. [Epub ahead of print]18(5):
    Advances of Cell Membrane-Coated Nanotechnology and Membrane Vesicles in Intestinal Targeted Drug Delivery Systems.
    Rou Tang, Fujun Zeng, Chengzhen Lyu, Jianyekai Tuerheng, Ziqi Guo, Kun He, Dong Wu.
      Although nanomedicine has enabled significant advances in drug delivery, the clinical translation of conventional synthetic nanocarriers is limited by immune clearance, non-specific biodistribution, and gastrointestinal instability. This poses major challenges for therapy targeting the intestines. Cell membrane-coated nanotechnology (CMCT) and membrane vesicle-based systems have emerged as biomimetic platforms integrating synthetic nanomaterials with naturally derived biological interfaces. These biohybrid systems inherit biological functions originating from cells, including immune evasion, prolonged circulation, lesion homing, and microenvironment-responsive interactions, through the direct transfer of intact membrane components. This review summarizes recent advances in CMCT and membrane vesicle-based strategies for intestinal drug delivery. It covers fabrication methodologies, programmable manufacturing approaches, and functional regulation enabled by diverse membrane sources and hybrid engineering designs. Applications in inflammatory bowel disease, colorectal cancer, and intestinal infections are highlighted, emphasizing key therapeutic mechanisms, such as targeting inflammation, neutralizing toxins, modulating the immune system, and regulating the microbiome. We also discuss the major challenges of translation, such as preserving membrane and coating integrity, ensuring oral stability, achieving batch reproducibility, and ensuring biosafety. Overall, this review establishes a conceptual and engineering framework to guide the transition of membrane-based nanocarriers from passive biomimicry to adaptive, clinically translatable intestinal delivery systems.
    Keywords:  biomimetic nanocarriers; cell membrane-coated nanoparticles; cell membrane-coated nanotechnology; intestinal drug delivery; membrane vesicles
    DOI:  https://doi.org/10.3390/pharmaceutics18050534
  53. Neural Regen Res. 2026 May 14.
    Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.
    Yao Wang, Zitong Wang, Jie Zhao, Yimin Zhou, Dong Wei, Jingjing Zhao, Zhongqing Sun, Wen Jiang.
      Mitochondrial transfer, the intercellular exchange of functional mitochondria, is crucial for maintaining cellular homeostasis and promoting tissue repair, particularly in neurological disorders associated with mitochondrial dysfunction. This review addresses the mechanisms through which mitochondrial transfer occurs, including tunneling nanotubes, extracellular vesicles, gap junction channels, and cell fusion. Mitochondrial transfer and transplantation have demonstrated positive therapeutic effects in various disease models, such as cerebral hemorrhage, ischemic stroke, Alzheimer's disease, and multiple sclerosis. Exogenous mitochondria can integrate into recipient cells, enhancing adenosine triphosphate production, restoring redox balance, and improving cellular survival under stress conditions. However, clinical translation faces significant hurdles, including immune rejection, limited recipient cell uptake capacity, a lack of standardized manufacturing protocols, and unresolved ethical concerns regarding mitochondrial sourcing. To address these challenges, cutting-edge biotechnological strategies, such as mitochondrial surface modification, nanocarrier-based delivery, biomaterial-assisted transplantation, and the use of engineered vesicles, are being developed to enhance the precision, stability, and biocompatibility of mitochondrial delivery. Furthermore, innovative approaches, including CRISPR-based genome editing, 3D-bioprinted tissue models, and artificial intelligence-assisted predictive platforms, are being explored to enhance mitochondrial function and delivery efficiency. Current strategies to harness mitochondrial transfer include pharmacological agents that enhance mitochondrial dynamics, stem cell-based delivery of healthy mitochondria, and the aforementioned bioengineered platforms. In conclusion, the integration of mitochondrial transfer as a groundbreaking treatment option for neurological disorders relies on addressing two to three fundamental challenges. These include the establishment of standardized and scalable protocols for production and quality control, formulating approaches to minimize immune reactions and improve the efficiency of mitochondrial integration, and creating a well-defined ethical and regulatory framework for sourcing and utilizing mitochondria. The primary contribution of this work lies in its integrated analysis of mechanistic insights, preclinical applications, and technological innovations, providing a consolidated roadmap for advancing mitochondrial transplantation from bench to bedside.
    Keywords:  artificial cells; biomaterial-assisted transplantation; extracellular vesicles; mesenchymal stem cells; mitochondrial dysfunction; mitochondrial surface modification; mitochondrial transfer; mitochondrial transplantation; neurological disorders; tunneling nanotubes
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01156
  54. Fish Shellfish Immunol. 2026 May 22. pii: S1050-4648(26)00351-7. [Epub ahead of print]175 111447
    Engineered Bacillus subtilis secreting piscidin-1/hepcidin enhances resistance against Aeromonas hydrophila in a zebrafish model.
    Ke-Yi Zhang, Wei-Yao Zhang, Jun-Xi Liu, Fang Qiao, Yuan Luo, Zhen-Yu Du, Mei-Ling Zhang.
      Antimicrobial peptides (AMPs) are effective against pathogens; however, their application in aquaculture remains limited due to low stability and poor delivery efficiency. In this study, we designed a xylose-induced-engineered probiotic to enable tightly controlled production and efficient targeted delivery of AMPs. Specifically, the tilapia-derived piscidin-1 and hepcidin were separately cloned into the Bacillus subtilis 168 (BS168) expression vector, resulting in the successful construction of two recombinant engineered strains-BS168-sfGFP-piscidin and BS168-sfGFP-hepcidin. These two engineered strains could significantly inhibit the growth of Aeromonas hydrophila compared with BS168 transformed with an empty vector (pSTOP1622) in vitro. To investigate the additive bacteriostatic activity, piscidin-1 and hepcidin were fused in tandem within the same expression vector, generating BS168-sfGFP-PH. These three engineered strains were orally administered to zebrafish to evaluate their antimicrobial efficacy in vivo. The results showed that zebrafish fed with BS168-sfGFP-PH exhibited the highest survival rate following A. hydrophila challenge. This protection was attributed to the strain's ability to reduce intestinal pathogen load, thereby suppressing inflammatory responses and improving intestinal integrity. Collectively, this work established an orally deliverable probiotic for secreting AMPs, serving as a promising strategy against bacterial infections in aquaculture.
    Keywords:  Aeromonas hydrophila; Antimicrobial peptides (AMPs); Bacillus subtilis; Bacterial-mediated delivery; Heterologous expression
    DOI:  https://doi.org/10.1016/j.fsi.2026.111447
  55. Cancers (Basel). 2026 May 20. pii: 1657. [Epub ahead of print]18(10):
    Diabetes-Driven Post-Translational Remodeling in Pancreatic Ductal Adenocarcinoma.
    Srikanth Kavyashree, Kannan Harithpriya, Kumar Ganesan, Kunka Mohanram Ramkumar.
      Diabetes mellitus (DM), particularly Type 2 DM (T2DM), is increasingly recognized as both a risk factor and an early manifestation of pancreatic ductal adenocarcinoma (PDAC), yet the molecular mechanisms bridging these conditions remain poorly understood. There is growing evidence that chronic metabolic stress in diabetes induces persistent cellular reprogramming and metabolic memory through stable post-translational and epigenetic alterations, independent of conventional insulin resistance, obesity, and inflammatory pathways. We aim to elucidate how hyperglycaemia and metabolic overload contribute to the accumulation of major intermediates, such as acetyl-CoA, Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), and reactive oxygen species, which induce broad changes in post-translational modifications in diabetes-induced PDAC. A comprehensive literature search was conducted using electronic databases, including PubMed, Scopus, and Web of Science databases, to retrieve studies published between 2005 and 2025. This review synthesizes current understanding of post-translational modifications (PTM) dynamics in diabetes-associated PDAC, with emphasis on their role in modulating oncogenic pathways such as KRAS-MAPK and PI3K-AKT. We introduce the concept of PTM remodeling, wherein transient metabolic perturbations become persistently stabilized, contributing to metabolic memory and tumor initiation. In addition, we examine how PTM-driven alterations influence the pancreatic tumor microenvironment, including stromal activation, immune evasion, and metabolic crosstalk, reinforcing a bidirectional link between tumor progression and systemic metabolic dysfunction. Furthermore, emerging therapeutic strategies targeting PTM-regulating enzymes, metabolic substrates, and signaling nodes are discussed as potential approaches to disrupt this axis. Collectively, precision targeting of PTM-mediated metabolic reprogramming represents a promising framework for early intervention and therapeutic development in PDAC associated with diabetes.
    Keywords:  PDAC initiation; PTM remodeling; epigenetic-metabolic crosstalk; metabolic memory; oncogenic signaling; post-translational modifications; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/cancers18101657
  56. Int J Mol Sci. 2026 May 12. pii: 4323. [Epub ahead of print]27(10):
    The Mechanistic Review of the Molecular Interface of RNA-Loaded Extracellular Vesicles: Redefining Targeted Therapy for Autoimmune Disorders.
    Aliya Orassay, Naizabek Yerzhigit, Anastassiya Ganina, Elmira Chuvakova, Oleg Lookin, Abay Baigenzhin.
      Traditional treatments of autoimmune diseases relying on systemic immunosuppression often lack curative potential and have severe side effects. Mesenchymal stem cells (MSCs) are a promising alternative due to their immunomodulatory properties; however, whole-cell therapies have certain limitations. MSC-derived extracellular vesicles (EVs), including small vesicles-exosomes-have emerged as a safe cell-free therapeutic platform capable of crossing biological barriers and delivering bioactive cargo with low immunogenicity. Various types of RNAs abundantly produced by host MSCs represent a key element of EV content. In particular, EVs carry small RNAs, which essentially determine cellular life and fate. Our review provides a comprehensive mechanistic framework for the use of RNA-loaded EVs, specifically those carrying microRNAs (miRNAs), small interfering RNAs (siRNAs), and messenger RNAs (mRNAs), in restoring immune homeostasis. We detail the biogenesis and molecular mechanisms governing sorting of RNA into EVs, along with endogenous and exogenous engineering strategies to enhance therapeutic potency. We examine how RNA-loaded EVs modulate immunological processes like reprogramming of macrophage M1-M2 polarization, Th17/Treg balance, and suppression of inflammatory signaling pathways such as NF-κB and the NLRP3 inflammasome. We address critical translational challenges-EV heterogeneity, manufacturing scalability, and need for standardized quality control-while outlining future opportunities for RNA-loaded EV-based therapeutics.
    Keywords:  RNA therapeutics; autoimmune diseases; extracellular vesicles; immunomodulation; mesenchymal stem cells; miRNA; siRNA
    DOI:  https://doi.org/10.3390/ijms27104323
  57. J Am Chem Soc. 2026 May 25.
    DNA-Targeted Sonodynamic Activation Enhances Antibacterial Efficacy in Deep and Hypoxic Infections.
    Yuling Xu, Lulu Yan, Chonglu Li, Lihui Zhao, Longcan Mei, Junhua Zhang, Shiming Liang, Junrong Li, Ruiping Zhang, Yao Sun, Jong Seung Kim.
      Deep-seated bacterial infections remain difficult to eradicate because both antibiotic delivery and photodynamic therapy are intrinsically constrained by tissue depth, biofilm protection, and hypoxic microenvironments. Sonodynamic therapy (SDT) offers noninvasive activation with clinically relevant penetration depth, but its antibacterial application has been limited by the scarcity of sonosensitizers that combine high activity, target specificity, and clinically relevant molecular scaffolds. Here, we establish TLD1433, a clinically advanced Ru(II) photosensitizer, as a DNA-targeting sonosensitizer for antibacterial therapy. Under ultrasound activation, TLD1433 exhibits strong sonodynamic activity, dominant singlet oxygen generation, and superior antibacterial efficacy relative to conventional sonosensitizers. Mechanistically, TLD1433 preferentially associates with bacterial DNA, thereby enabling localized oxidative damage to an essential intracellular target. In parallel, it catalyzes endogenous H2O2 decomposition to generate O2, thereby relieving biofilm hypoxia and amplifying sonodynamic efficacy. As a result, ultrasound-activated TLD1433 shows potent antibacterial efficacy in a murine Pseudomonas aeruginosa pneumonia model and in patient-derived bronchoalveolar lavage fluid under deep-tissue conditions. This work establishes a mechanistically distinct antibacterial sonodynamic strategy based on a clinically advanced ruthenium complex, providing a design framework for target-specific sonosensitizers against deep and hypoxic bacterial infections.
    DOI:  https://doi.org/10.1021/jacs.6c06618
  58. Regen Biomater. 2026 ;13 rbag029
    Engineered nanomedicine triggering ROS storms for enhanced cancer therapeutics.
    Yuebing Hou, Xiaoxuan Hou, Yiyao Wang, Chu Chu, Liya Tian, Nengyi Ni, Peiji Song, Yuchun Wei, Xiao Sun.
      Reactive oxygen species (ROS) play a significant role in regulating various signaling pathways and biochemical reactions within cells during their proliferation and differentiation. Nonetheless, when excessive ROS are accumulated within cells, they will cause severe damage to cellular components like DNA, proteins and lipids. With advances in nanotechnology, 'ROS storm' has become a promising multifaceted therapeutic strategy for tumor treatment, whose mechanism mainly lies in inducing a massive ROS surge within tumors via synthesis optimization, the modulation of tumor adaptive responses and overcoming inherent constraints of individual ROS, so as to exceed the fatal threshold, thereby leading to severe oxidative damage. Therefore, in this review, we would like to focus on the specific strategies of engineered nanomaterials for triggering ROS storms in tumor tissues and the resultant effects, which have been primarily described in terms of augmenting substrate supply, inhibiting antioxidant systems, enhancing catalytic efficiency, enriching the diversity of reactive species and intensifying targeting accumulation, respectively. Moreover, the strong potential of combining this strategy with therapies such as immunotherapy has been demonstrated in various studies and constitutes a key focus of our discussion. At the end of the review, the future outlook and the remaining challenges when it comes to clinical application have also been discussed. This review is aimed at providing an overview of previous anti-cancer studies based on ROS storm, and shedding new light on this innovative strategy with fresh perspectives, thereby facilitating advances in cancer nanomedicine.
    Keywords:  ROS storm; cancer treatment; nanomedicine; oxidative stress
    DOI:  https://doi.org/10.1093/rb/rbag029
  59. J Nanobiotechnology. 2026 May 29.
    Nano-armed bcg delivers Cu-Fe MOF to trigger dual cell death in bladder cancer.
    Yang Li, Fangdie Ye, Gang Liu, Lili Cheng, Yang Song, Shijie Zhang, Bo Li.
      Intravesical Bacillus Calmette-Guérin (BCG) perfusion is widely regarded as a standard clinical intervention for non-muscle-invasive bladder cancer. Despite its established efficacy, this treatment is associated with a high tumor recurrence rate of approximately 50%, highlighting a significant clinical challenge. To address this limitation, combination strategies integrating BCG with other antitumor modalities have emerged as a promising direction for enhancing therapeutic outcomes. In this study, we engineered a novel "super-BCG" formulation by functionalizing BCG with a copper-iron metal-organic framework (CuFe MOF). This composite system leverages the natural tropism of BCG toward bladder tumor sites to achieve targeted delivery of the MOF directly into the tumor microenvironment. Once localized, the CuFe MOF induces synergistic cuproptosis and ferroptosis, two distinct forms of regulated cell death, thereby overcoming the constraints of monotherapeutic approaches that rely on a single death mechanism. This dual induction not only promotes robust tumor cell death but also potentiates antitumor immune activation by stimulating immunogenic cell death. Furthermore, the MOF works in concert with BCG's inherent immunoadjuvant properties, resulting in a comprehensive enhancement of antitumor immunity and significantly improved immunotherapeutic efficacy. In summary, we have developed a nano-armed BCG-based therapeutic platform that integrates targeted drug delivery with dual-mode cell death induction and immune activation, offering a potent and versatile strategy for the treatment of bladder cancer.
    Keywords:  Bacillus Calmette–Guérin (BCG); Bladder Cancer Immunotherapy; Cuproptosis and Ferroptosis; Metal–Organic Framework (CuFe MOF); Targeted Drug Delivery
    DOI:  https://doi.org/10.1186/s12951-026-04590-0
  60. Acta Biomater. 2026 May 28. pii: S1742-7061(26)00336-3. [Epub ahead of print]
    An optimised lipid nanoparticle platform enables efficient CRISPR/Cas9 genome editing in hard-to-transfect cells.
    Xinpu Yang, Rui Sang, Gyorgy Hutvagner, Alex W Hewitt, Diangeng Li, Yi Li, Wei Deng.
      CRISPR/Cas9 is a powerful tool for genome editing and functional gene studies, but its therapeutic potential is often hampered by inefficient transfection, particularly in hard-to-modify cell types. In this study, we developed and optimised a lipid nanoparticles (LNPs) platform that enhances CRISPR/Cas9-mediated genome editing across diverse cell types, including those that are difficult to modify using commercially available lipid-based delivery agents. Our engineered LNPs exhibit consistent particle size below 100 nm, low polydispersity and high encapsulation efficiency. Using this platform, GFP knockout in HEK-293 cells reached 78.7%, and maintained consistent efficiency after lyophilisation and reconstitution. Knockout of the LCN2 gene in MDA-MB-231 cells resulted in a 90.8% reduction in mRNA expression, outperforming the 51.1% reduction achieved using CRISPRMAX Lipofectamine, and functional assays confirmed that LCN2 disruption significantly inhibited cell proliferation and migration. Co-delivery of CRISPR/Cas9 and a GFP HDR template enabled precise knock-in, achieving >20% efficiency in HEK-293 cells and >8% in MSCs and DC2.4 cells, significantly outperforming Lipofectamine 3000 transfection reagent. Given the rapid expansion of CRISPR applications in biomedical research, our LNP-based delivery system represents a promising non-viral platform with broad potential for therapeutic applications, particularly in hard-to-modify cell types. STATEMENT OF SIGNIFICANCE: CRISPR/Cas9 is a transformative gene-editing technology for functional genomics and therapeutic development; however, its widespread application is constrained by the lack of safe and efficient delivery systems, particularly for hard-to-transfect cell types. Lipid nanoparticles (LNPs) represent a promising non-viral delivery strategy, yet their transfection efficiency varies substantially across cell lines due to differences in cellular membrane properties. Here, we developed and optimized an LNP platform that enables highly efficient Cas9/sgRNA-mediated gene knockout and knock-in across multiple challenging cell types, consistently outperforming commercial transfection reagents. The findings establish this LNP system as a versatile and effective non-viral platform for CRISPR/Cas9-mediated genome editing, overcoming key limitations of existing commercial lipid-based delivery agents in hard-to-modify cell types and offering a promising strategy for future clinical translation.
    Keywords:  CRISPR/Cas9; Gene editing; Hard-to-transfect cells; Lipid nanoparticles
    DOI:  https://doi.org/10.1016/j.actbio.2026.05.044
  61. Biomedicines. 2026 May 13. pii: 1101. [Epub ahead of print]14(5):
    Novel Mechanistic Insights into Primary Biliary Cholangitis: From Pathogenesis to Mesenchymal Stem Cell-Mediated Repair.
    Zhenxia Huang, Meiling Zhang, Xiaoyue Zhang, Yao Ge, Cuifang He, Junfeng Li.
      Primary biliary cholangitis (PBC) is an autoimmune-mediated cholestatic liver disease characterized by the progressive destruction of intrahepatic bile ducts, which ultimately leads to hepatic fibrosis and cirrhosis. The current first-line therapy, ursodeoxycholic acid, is associated with a high rate of non-response. Moreover, second-line treatments are constrained by variable efficacy and safety concerns. Mesenchymal stem cells (MSCs), owing to their potent immunomodulatory and tissue-repairing capabilities, represent a promising new therapeutic strategy for PBC patients with poor response to conventional therapies. This review systematically outlines the pathogenesis of PBC, focusing on factors including genetics, environment, and immune dysregulation. Furthermore, it examines recent evidence on the mechanisms by which MSCs and their derivatives, such as exosomes, may intervene in PBC progression through immunomodulation, anti-fibrotic effects, and potential hepatic differentiation. This paper also reviews the current status and challenges of the clinical translation of MSCs therapy, and proposes that engineered modification and standardized preparation are the key directions to promote its application. In conclusion, this review provides a theoretical foundation and future directions for deepening the understanding of PBC pathogenesis and developing novel MSC-based therapeutic strategies.
    Keywords:  exosomes; extracellular vesicles; mesenchymal stem cells; primary biliary cholangitis; therapy
    DOI:  https://doi.org/10.3390/biomedicines14051101
  62. Nucleosides Nucleotides Nucleic Acids. 2026 May 24. 1-21
    Gene therapy, RNA-based drugs, and CRISPR in neuroprotection.
    Aleena Taufiq, Sajad Ahmad Dar, Saurabh Singh, Arshad Jawed, Taru Singh.
      Neurodegenerative diseases are associated with progressive neural malfunction, which is driven by common molecular pathologies that encompass protein aggregations, mitochondrial dysfunction, aberrant RNA metabolism and impaired intracellular clearance. Conventional treatments are largely symptomatic with no treatment of the underlying pathology. Gene therapies, RNA-based therapeutic platforms and CRISPR-based genome-editing technologies provide more targeted methods to regulate the pathological pathways and restore neuronal homeostasis. Nevertheless, these interventions can have transient, reversible or long-term effects instead of a consistent irreversible effect depending on the platform being used. Engineered viral vectors, particularly adeno-associated viruses, enable cell-type-specific and circuit-resolved delivery within the central nervous system. Although constrained by a limited packaging capacity (∼4.7 kb), innovations such as dual-vector systems and capsid engineering are expanding their functional utility. RNA therapeutics, such as antisense oligonucleotides, siRNA/miRNA and synthetic mRNA, provide reversible gene expression regulation, whereas CRISPR can be used to disrupt, correct or regulate the expression of specific genes. Together, these platforms constitute a multifaceted and evolving toolkit for neuroprotection, with the potential to modify disease progression in neurodegenerative disorders. However, most approaches remain at preclinical or early clinical stages, and further validation is required to establish long-term efficacy and safety.
    Keywords:  CRISPR genome editing; Neurodegenerative diseases; RNA-based therapeutics; adeno-associated virus vectors; gene therapy
    DOI:  https://doi.org/10.1080/15257770.2026.2662373
  63. Transl Oncol. 2026 May 26. pii: S1936-5233(26)00158-0. [Epub ahead of print]70 102821
    Sotorasib combined with 3-methyladenine for the treatment of KRAS G12C-mutant pancreatic cancer and its underlying mechanisms.
    Yukun Li, Mengmeng Zhou, Jingjing Pan, Haochen Su, Mengke Song, Zujiao Guan, Danmai Zhao, Xiaoxin Zhao, Yiqi Zhao, Pu Chen, Shu Zhang, Ying Lv.
      Pancreatic cancer is a gastrointestinal malignancy with an insidious onset and rapid progression. Due to limited therapeutic strategies, its mortality remains high. The KRAS gene is among the most frequently mutated genes in solid tumors, and the development of drugs targeting KRAS mutations in pancreatic cancer is a current research focus. Sotorasib (AMG510) is the first small-molecule KRAS G12C-targeted inhibitor approved by the FDA for clinical use and has demonstrated safety and antitumor activity in tumors such as colorectal cancer and non-small cell lung cancer. At present, studies on the mechanisms of AMG510 in KRAS G12C-mutant pancreatic cancer are still at an early stage. This study aimed to investigate the effects of AMG510 on KRAS G12C-mutant pancreatic cancer cells and to preliminarily explore its mechanism of action. AMG510 inhibited the initiation and progression of KRAS G12C-mutant pancreatic cancer by inducing reactive oxygen species (ROS) accumulation, mitochondrial damage, cell cycle arrest, and apoptosis. RNA-seq revealed that AMG510 triggered cytoprotective autophagy in KRAS G12C-mutant pancreatic cancer. Treatment with the combination of AMG510 and the early autophagy inhibitor 3-methyladenine(3-MA) further suppressed proliferation and promoted apoptosis. Mouse experiments confirmed the biosafety and efficacy of AMG510 combined with 3-MA in vivo. The results of this study revealed that AMG510 exhibited favorable antitumor activity against KRAS G12C-mutant pancreatic cancer in vitro and in vivo, and the combination of AMG510 and 3-MA may represent a candidate therapeutic regimen for the clinical treatment of KRAS G12C-mutant pancreatic cancer.
    Keywords:  3-MA; AMG510; Apoptosis; Autophagy; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.tranon.2026.102821
  64. J Nanobiotechnology. 2026 May 27.
    Exosome-mimetic nanocarriers in cancer diagnosis and drug delivery: engineering strategies, functional biomimicry, safety considerations, and clinical translation.
    Lorena Duarte-Peña, Sheila I Peña-Corona, Fabiola V Borbolla-Jiménez, Juan Isaac Chávez-Corona, Hernán Cortés, Gareth Omar Rostro-Alonso, Octavio Daniel Reyes-Hernández, Gabriela Figueroa-González, Gerardo Leyva-Gómez, Javad Sharifi-Rad, William C Cho.
      Cancer remains one of the leading causes of mortality worldwide, driving the development of advanced drug delivery systems to improve therapeutic selectivity and overcome the complex defense mechanisms of malignant cells. Exosome-mimetic nanocarriers (EMNs) have emerged as an advanced biomimetic platform for cancer diagnosis and targeted drug delivery, combining the biological functionality of natural exosomes with the manufacturing flexibility and scalability of synthetic nanocarriers. This review analyzes the composition, design, and architecture of EMNs, as well as their applications in cancer drug delivery, drawing on fundamental concepts of pharmaceutical technology to provide a translational perspective. It also includes a dedicated section on cancer diagnosis and theranostic platforms, as well as a critical analysis of recent technological advancements in exosome-mimetic systems. Although the clinical translation of natural exosomes remains limited, emerging evidence suggests that engineered EMNs offer improved scalability, reproducibility, and therapeutic versatility. Recent studies highlight their potential to overcome key limitations of natural vesicles, positioning them as promising candidates for future clinical translation and commercialization.
    Keywords:  Biomimetic drug delivery; Cancer, exosome-mimetic nanocarriers; Extracellular vesicles; Targeted nanomedicine
    DOI:  https://doi.org/10.1186/s12951-026-04612-x
  65. J Biomater Sci Polym Ed. 2026 May 29. 1-32
    Recent Advancements and Applications of Quantum Dots in Tissue Engineering.
    Srija Sur, Neha Imtiaz, Soumyarup Dutta, Arijit Mondal, Shounak Sarkhel, Rajarshi Nath, Debanjan Sen, Vaibhav Rathore, Arindam Maity.
      Tissue engineering is a rapidly advancing interdisciplinary field focused on restoring or replacing damaged tissues using engineered biological substitutes. This is commonly achieved by culturing cells on three-dimensional biodegradable scaffolds that support cell adhesion, proliferation, and extracellular matrix formation during scaffold degradation. Quantum dots (QDs), a class of inorganic nanofluorophores, have attracted significant attention due to their unique optical, physicochemical, and biofunctional properties. Through core-shell engineering and surface functionalization, QDs can be tailored to enhance biocompatibility and target specificity. They have broad biomedical applications, including bioimaging, targeted drug and gene delivery, in vivo cell tracking, and real-time tissue monitoring. In tissue engineering, QDs improve scaffold performance, guide stem cell differentiation, and support organ-specific tissue regeneration. Their high-resolution imaging capability enables continuous monitoring of tissue development and healing. QDs also show promise in regenerative medicine by modulating immune responses and promoting tissue repair, particularly in skeletal tissues. Despite challenges such as limited aqueous solubility, potential cytotoxicity, and biodistribution issues, advances in bioconjugation with peptides, polymers, and targeting ligands have significantly improved their safety. With continued research, QDs hold immense potential in personalized and precision medicine by integrating diagnostic and therapeutic functions within a single nanosystem.
    Keywords:  Quantum dots; regenerative medicine; scaffolds; tissue engineering
    DOI:  https://doi.org/10.1080/09205063.2026.2678316
  66. Biomaterials. 2026 May 23. pii: S0142-9612(26)00357-1. [Epub ahead of print]335 124333
    Dual-functional poly(disulfide) enables "Once-and-for-all" atherosclerosis therapy via precision hepatocyte base editing.
    Xiaoping Zhang, Shijuan Gao, Danyang Chen, Hongying Wang, Minzan Zuo, Leyong Wang, Qing-Wen Zhang, Ruibing Wang.
      CRISPR-based base editors hold transformative potential for genetic medicine, but their clinical translation is hampered by the need for cell-specific delivery, efficient cytosolic release, and durable activity. Here, we report a dual-functional poly(disulfide) that simultaneously achieves both hepatocyte-specific targeting and direct cytosolic delivery of adenine base editors (ABEs). By displaying galactose ligands for binding to asialoglycoprotein receptors (ASGPRs) on hepatocytes, our polymer enables specific recognition of hepatocytes. Crucially, the poly(disulfide) backbone then facilitates direct cytosolic delivery via thiol-disulfide exchange, bypassing endosomal entrapment. This dual-function system mediates efficient ABEs delivery to hepatocytes, resulting in durable editing of the ANGPTL-3 gene after a single administration. In a mouse model of atherosclerosis, this one-dose treatment produced sustained reductions in low-density lipoprotein cholesterol and significantly attenuated plaque formation. To our knowledge, this represents the first successful application of base editing for the effective prevention and treatment of atherosclerosis with a single-dose. Our work establishes a "once-and-for-all" atherosclerosis treatment that creates a transformative platform for precision genome medicine in atherosclerosis and other metabolic diseases.
    Keywords:  Atherosclerosis; Base editing; Cytoplasmic delivery; Polydisulfide; Prevention and treatment
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124333
  67. bioRxiv. 2026 May 12. pii: 2026.05.07.723637. [Epub ahead of print]
    Discovery and Characterization of Interleukin-4-Specific Affibodies for Affinity-Controlled Protein Release and Macrophage Polarization.
    Jonathan Dorogin, Astha Lamichhane, Andy J Huang, Justin E Svendsen, Morrhyssey A Benz, Shreya A Raghavan, Marian H Hettiaratchi.
      Interleukin-4 (IL-4) is a key immunoregulatory cytokine that promotes type 2 inflammation, drives macrophage polarization toward an anti-inflammatory M2 phenotype, and supports tissue repair. However, clinical translation of IL-4 therapies to modulate the immune response is limited by the need for precise control over its delivery to avoid immune dysregulation. Here, we report an affinity-based strategy to modulate IL-4 delivery and bioactivity using engineered affibody proteins. A yeast surface display library was screened via magnetic- and fluorescence-activated cell sorting to identify two IL-4-specific affibodies with moderate binding affinities (dissociation constants, K D = 459 and 141 nM). Circular dichroism confirmed expected alpha-helical folding, and biolayer interferometry characterized the kinetics of IL-4 binding. Structural modeling using AlphaFold3 and RosettaDock and molecular dynamics simulations using GROMACS predicted distinct binding sites for each IL-4-specific affibody on the IL-4 protein and suggested potential interference with receptor complex formation. Bioactivity studies using murine bone marrow-derived macrophages demonstrated that IL-4 complexed with affibodies maintained Ym1 gene expression but significantly reduced Ym1 protein levels, indicating partial inhibition of IL-4 signaling. To enable controlled cytokine delivery via affinity interactions, affibodies were conjugated to polyethylene glycol maleimide (PEG-mal) hydrogels, which were loaded with IL-4. Affibody-conjugated hydrogels achieved high IL-4 loading efficiency (>90%) and exhibited sustained release over 7 days. Increasing affibody-to-IL-4 ratios significantly reduced both the rate and total amount of cytokine release. Overall, this work establishes IL-4-specific affibodies as versatile tools for tuning cytokine presentation and modulating bioactivity and provides a promising approach for regulating inflammatory responses and advancing cytokine-based therapies with improved temporal control.
    DOI:  https://doi.org/10.64898/2026.05.07.723637
  68. Mater Horiz. 2026 May 27.
    A multifunctional nanobooster to restore ceftazidime susceptibility in mucoid Pseudomonas aeruginosa.
    Jia Ma, Yiwen Yuan, Xiaoyuan Ji, Na Jiang, Jiye Zhang, Xiaojiao Li, Xinghui Liu, Chang Liu.
      Mucoid Pseudomonas aeruginosa (m.PAE) presents a major clinical challenge due to its high resistance to ceftazidime (CAZ), a cornerstone antibiotic. This resistance is orchestrated through three barriers, including the formation of an alginate-rich mucoid biofilm that limits drug penetration, upregulated efflux pumps such as MexAB-OprM that reduce intracellular CAZ accumulation, and expression of β-lactamases that hydrolyze CAZ. To address these barriers simultaneously, we engineered a multifunctional nanobooster termed A/C-pAg3PO4, which integrates a silver phosphate nanoparticle (NAg3PO4) core for bacterial disruption, a carboxyl-PEG coating (pAg3PO4) to improve biofilm penetration, and dual co-loading of avibactam (AVB) to inhibit β-lactamase and carbonyl cyanide m-chlorophenylhydrazone (CCCP) to block efflux pumps. In vitro, A/C-pAg3PO4 showed potent antibacterial efficacy, penetrated mucoid biofilms efficiently, and restored bacterial susceptibility via metabolic reprogramming. In murine models of acute pneumonia and lethal sepsis, it markedly reduced bacterial load, mitigated inflammatory damage, and achieved complete survival with no evident toxicity. Our work thus provides a promising strategy to overcome m.PAE resistance to CAZ by concurrently targeting its key defensive mechanisms.
    DOI:  https://doi.org/10.1039/d6mh00262e
  69. J Nanobiotechnology. 2026 May 26.
    An in situ generated CAR-M with IFN-γ and negative dominance Sirpα isoform augments hepatocellular carcinoma immunotherapy.
    Xiang Li, Jing Hu, Tian Zhang, Hongceng Li, Quanrong Lai, Tao Wang, Yuxin Liu, Lan Zhang, Yonglong Wei, Shi Wei, Panpan Zhang.
       BACKGROUND AND AIMS: Chimeric antigen receptor (CAR) T cells have shown strong efficacy in hematological cancers but limited success in solid tumors. Macrophages, with their natural ability to infiltrate tumors, modulate immunity, and phagocytose cancer cells, offer a promising alternative when engineered with CARs. While studies have demonstrated the feasibility and anti-tumor activity of CAR macrophages (CAR-M), enhancing their persistence and phagocytic capacity remains a key challenge.
    METHODS AND RESULTS: Building on first-generation CD3ζ-based CAR-M, we developed a novel CAR targeting human GPC3, incorporating IFN-γ and the extracellular domain of SIRPα (SIRPαECD) to improve CAR-M persistence and block the CD47-SIRPα immune checkpoint. Following delivery via lipid nanoparticle-encapsulated mRNA (LNP-mRNA), the self-secreted IFN-γ sustained M1 polarization through phospho-STAT1 activation. Meanwhile, the ectopically expressed SIRPαECD competitively bound to CD47 on tumor cells, thereby blocking the endogenous SIRPα-SHP2 interaction in a dominant-negative manner. This design enhanced pro-inflammatory activity and anti-tumor efficacy compared to CD3ζ-only CAR-M. Single-cell RNA sequencing and cellular analysis showed that in situ programmed CAR-M reprogrammed the tumor microenvironment toward inflammation in a murine hepatocellular carcinoma (HCC) model. Moreover, CAR-M derived from human peripheral blood mononuclear cells (PBMCs) effectively phagocytosed human HCC organoids while sparing healthy tissues, indicating clinical potential.
    CONCLUSIONS: Collectively, our work presents a novel CAR design that enhances phagocytic function and sustains anti-tumor activity, offering a promising strategy for human solid tumor immunotherapy.
    DOI:  https://doi.org/10.1186/s12951-026-04593-x
  70. Photodiagnosis Photodyn Ther. 2026 May 28. pii: S1572-1000(26)00195-X. [Epub ahead of print] 105528
    Photodynamic Therapy Improves Sensitivity to Temozolomide in Glioblastoma Cells via Inhibiting Autophagy.
    Kuiyuan Hou, Chen Zhao, Weijun Wang, Song Li.
       OBJECTIVE: Chemotherapy resistance from temozolomide (TMZ) continues to be a major cause of glioblastoma (GBM) recurrence. Emerging evidence indicates that cytoprotective autophagy constitutes a key resistance mechanism​ to TMZ. Photodynamic therapy (PDT) has been shown to modulate the sensitivity of glioblastoma cells (GCs) to TMZ through multiple pathways. This study aims to explore how PDT regulates the sensitivity of GCs to TMZ chemotherapy by inhibiting autophagy formation.
    METHODS: The vitality and proliferation ability of U251 cells were evaluated under different treatments using cell counting kit-8 (CCK-8), colony formation, and fluorescence assays, respectively. The reactive oxygen species (ROS) levels were measured using the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence probes. The features of autophagy were assessed via lysosomal fluorescent probes, monodansylcadaverine (MDC) staining, and transmission electron microscopy (TEM).
    RESULTS: Compared to TMZ group, samples treated with the combination of TMZ and PDT showed a marked reduction in both cell viability and proliferative ability. Despite this anti-tumor effect, cell death, as assessed by propidium iodide (PI) staining, was not significantly increased during the first 4 hours of the combination treatment. But the fluorescence intensity of ROS was significantly higher in Combination group, compared with the other group. The fluorescent analyses and TEM observations confirmed an increase in cytoprotective autophagy in the late phase of TMZ therapy. However, the PI staining assay revealed that the TMZ with synergistic PDT enhanced the percentage of GCs death.
    CONCLUSION: The combination of TMZ and PDT suppresses autophagy by increasing ROS levels, thereby improving the sensitivity of GCs to TMZ chemotherapy. This finding represents a novel biomedical engineering strategy to overcome TMZ resistance.
    Keywords:  Autophagy; Glioblastoma cells; Photodynamic therapy; Sensitivity; Temozolomide
    DOI:  https://doi.org/10.1016/j.pdpdt.2026.105528
  71. J Appl Biomater Funct Mater. 2026 Jan-Dec;24:24 22808000261456607
    Stimuli-responsive microneedles: Engineered solutions for multifaceted diabetic wound healing.
    Fengyuan Wang, Jue Zhang, Bing Han, Ming Chen, Xiyu Wang, Ke Wang, Jiaxi Kou, Guopu Chen, Fenghua Sun.
      Diabetic wounds are among the most common complications in patients with diabetes, often occurring in the lower extremities and manifesting as diabetic foot ulcers. These wounds are often associated with issues such as infection, peripheral artery disease, hyperglycemia, and hypoxia, making them difficult to heal and prone to becoming chronic wounds. MNs enable painless, controlled transdermal drug delivery, overcoming limitations of traditional methods such as poor permeability and short drug duration. Stimuli-responsive microneedles targeting specific triggers have developed rapidly in recent years and are expected to contribute to the realization of precision medicine. Diabetic wounds are often accompanied by microenvironmental imbalance, and this complex wound milieu frequently causes them to progress into refractory wounds. Stimuli-responsive microneedles therefore represent a promising therapeutic strategy. Current studies in this field are still mainly limited to single-stimulus-responsive microneedles, whereas multifunctional microneedles capable of responding to multiple stimuli have not yet been fully developed. This review summarizes the research foundation and current progress of stimuli-responsive microneedles for the treatment of diabetic wounds, and further discusses the future prospects and potential directions of multi-stimuli-responsive microneedles. In addition, this review clarifies the conceptual boundary between truly stimuli-responsive microneedles and microenvironment-associated therapeutic platforms, compares major responsive strategies and microneedle platforms, and discusses key translational barriers including mechanical robustness, manufacturing scalability, cargo stability, model relevance, and regulatory considerations.
    Keywords:  diabetic ulcer; drug delivery; microneedles; stimulus response; wound healing
    DOI:  https://doi.org/10.1177/22808000261456607
  72. Biomaterials. 2026 May 19. pii: S0142-9612(26)00344-3. [Epub ahead of print]335 124320
    Modularly designed hybrid vesicles as dual-adjuvant nanovaccines for cancer immunotherapy.
    Yuanwei Pan, Yuji Tang, Lefan Chen, Yangtao Xu, Xinyao Hu, Jing Zhang, Yongfa Zheng, Peng She, Lang Rao, Ximing Xu.
      Natural extracellular vesicles (EVs) and extruded membrane vesicles (MVs) have emerged as a promising platform for cancer vaccination by co-delivering tumor antigens and adjuvant. However, conventional designs rely on a single class of adjuvant, which often fail to adequately activate dendritic cells (DCs), resulting in inefficient cross-priming and weak cytotoxic T lymphocyte (CTL) activation. To address this, we designed a dual-adjuvant nanovaccine by modularly fusing interferon-alpha (IFNα)-displaying bacterial MVs (IFNα-BMVs) with programmed cell death protein 1 (PD1)-displaying cancer MVs (PD1-CMVs) to potentiate antitumor immune responses. In this design, IFNα-BMVs deliver dual-adjuvant pathogen-associated molecular patterns (PAMPs) and IFNα to promote DC maturation and cross-priming, thereby activating CTL. Concurrently, PD1-CMVs provide tumor-associated antigens (TAAs) and utilize membrane-anchored PD1 as a decoy receptor for targeted PD-L1 blockade, thus preventing CTL exhaustion. More importantly, this IFNα and PD1 co-displaying hybrid MVs (IP-HMVs) nanovaccine significantly upregulated costimulatory molecules and antigen-presenting molecules, thereby promoting DC maturation and CTL infiltration. Furthermore, RNA sequencing analysis validated that IP-HMVs robustly activated canonical antigen presentation pathways. In both subcutaneous and metastatic 4T1 tumor models, IP-HMVs significantly suppressed tumor progression and extended median survival to 35 days. The modular design offers a generalizable framework for developing next-generation cancer vaccines.
    Keywords:  Cancer immunotherapy; Dual-adjuvant; Hybrid membrane vesicles; Interferon-alpha; Nanovaccine
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124320
  73. Mol Ther. 2026 May 26. pii: S1525-0016(26)00404-1. [Epub ahead of print]
    Engineering human T cells with antigen receptors for immune regulation in autoimmune disease and transplantation.
    Sonya Mangat, Karoliina Tuomela, Megan K Levings.
      Engineered cell therapies have revolutionized the treatment of immune disorders; most notably, chimeric antigen receptors (CARs) have been used to generate antigen-specific T cells capable of targeting and eliminating tumours. Ongoing research extends similar principles to induce immune tolerance in autoimmune diseases and transplantation, by leveraging the immunosuppressive properties of regulatory T cells (Tregs) and co-opting conventional T cells for tolerogenic applications. In this review, we highlight the diverse use of engineered antigen receptors to generate human T cell-based therapies, spanning a variety of disease contexts and focussing primarily on CAR Tregs. We further summarize work that aims to improve therapeutic potency and safety, including approaches to enhance suppressive pathways and optimize antigen receptor design and regulation. Finally, as CAR Tregs and similar therapies move to the clinic, we discuss the practical implications of translation and methods that utilize off-the-shelf products and in vivo gene delivery.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.05.017
  74. Front Oncol. 2026 ;16 1779803
    A novel auto-fluorescent porphyrin-lipid nanoparticle strategy for CTNNB1 gene silencing in hepatocellular carcinoma.
    Jeffrey C To, Alyssa Apilan, Elisa Pasini, Yulin Mo, Juan Chen, Anita Bakrania, Jiachuan Bu, Anni Pan, Oyedele Adeyi, Arndt Vogel, Gang Zheng, Mamatha Bhat.
       Background: Hepatocellular carcinoma (HCC) remains a high-fatality cancer with limited effective therapies. CTNNB1 mutations, frequently observed in HCC, are associated with poor prognosis and immune evasion. CTNNB1 has long been considered an undruggable target due to its structural characteristics and extensive protein interactions. Porphyrin lipid nanoparticles (porphyrin-LNPs) are capable of targeting liver tumor cells, and their inherent autofluorescence allows evaluation of nanoparticle biodistribution in the liver. Our goal was to formulate a porphyrin-LNP encapsulating CTNNB1-targeting siRNA, as a novel strategy to target β-catenin-driven HCCs.
    Methods: We developed porphyrin-LNPs for systemic delivery of CTNNB1-targeting siRNA. Porphyrin-LNPs were synthesized via microfluidic rapid mixing and characterized by cryo-TEM and dynamic light scattering. Their delivery efficacy was validated in HCC cell lines (Hep3B, HepG2), and their therapeutic potential was evaluated in a murine model of CTNNB1/KRAS-driven HCC.
    Results: Porphyrin-LNPs showed high encapsulation efficiency (97%) and effective siRNA delivery in vitro. Treatment with porphyrin-LNP-si-CTNNB1 resulted in approximately 90% downregulation of CTNNB1 expression (p < 0.0001 in Hep3B at 50nM; p < 0.0001 in HepG2 at 10nM) and significantly reduced clonogenic survival in both Hep3B (50% reduction at 50nM, p < 0.0001) and HepG2 (75% reduction at 10nM, p < 0.001) cell lines. In vivo, porphyrin-LNP-si-CTNNB1 significantly reduced tumor burden by approximately 67% (p < 0.0001), liver-to-body weight ratio by 50% (p < 0.0001), histological tumor grade, and β-catenin expression in CTNNB1/KRAS-driven HCC mice by approximately 58% (p < 0.0001).
    Conclusions: This study demonstrated that porphyrin-LNPs can effectively deliver siRNA to silence CTNNB1, an oncogene that has so far been undruggable in HCC. Future studies should explore biodistribution, immune modulation, and combination strategies to enhance clinical translatability of CTNNB1-targeted RNA interference in HCC.
    Keywords:  CTNNB1; RNA interference; hepatocellular carcinoma (HCC); lipid nanoparticles (LNPs); porphyrin-lipid nanoparticles; targeted gene therapy; β-catenin
    DOI:  https://doi.org/10.3389/fonc.2026.1779803
  75. Int Dent J. 2026 May 27. pii: S0020-6539(26)00221-2. [Epub ahead of print]76(4): 109627
    Middle-Term Follow-Up Outcomes of the Customised Temporomandibular Joint-Skull Base Combined Prosthesis by 3D Printing.
    Qingyu Xu, Yuxin Zhang, Xiang Wei, Liang Huo, Zixiang Han, Lingtong Bu, Minjie Chen, Jisi Zheng, Chi Yang.
       INTRODUCTION: The combined lesions of the temporomandibular joint (TMJ) and skull base pose a considerable clinical challenge, frequently necessitating complex reconstructive procedures, yet established treatment protocols remain insufficient. This case series aims to assess the middle-term clinical safety, accuracy, and efficacy of our own customised temporomandibular joint-skull base combined prosthesis by 3D printing.
    METHODS: This is a prospective single-centre consecutive case series study and planned to enrol 12 patients. Patients with TMJ-skull base combined lesions who visited the Department of Oral Surgery of our hospital from September 2016 to April 2024 were recruited. General conditions, clinical examinations, and radiological evaluations were conducted preoperatively and at 1 month, 3 months, 6 months, 1 year, 2 years, and possibly beyond 3 years postoperatively. Computed tomography scans were used to assess prosthesis position and bone contact. The 10 cm visual analogue scale (VAS) was used to assess pain, diet, and mandibular function. Objective evaluations included maximum internal opening, deviation of opening, and maximum mandibular forward and lateral movement. SPSS software was employed for data analysis.
    RESULTS: A total of 12 patients (6 females and 6 males, with an average age of 46.58 ± 12.17 years) were included; all patients underwent prosthesis implantation. After a follow-up period of 3.85 ± 2.63 years, patients showed no adverse symptoms such as infection and cerebrospinal fluid leakage. The occlusion and face type were stable. The prosthesis did not exhibit significant loosening, displacement, or fracture, and all had good bone integration. Postoperative pain, diet, mandibular function, and maximum internal opening underwent significant enhancement, whereas deviation of opening and mandibular movement towards the non-diseased side remained unchanged.
    CONCLUSION: The customised TMJ-skull base combined prosthesis developed in this study exhibited favourable mid-term clinical safety, accuracy, and efficacy in its application.
    CLINICAL RELEVANCE: Our findings offer promising prospects in and clinical translational value in terms of development of TMJ and skull base reconstruction technology in future.
    Keywords:  Case series; Clinical application; Customised prosthesis; Oral and maxillofacial surgery; Skull base; Temporomandibular joint
    DOI:  https://doi.org/10.1016/j.identj.2026.109627
  76. Plant Cell Rep. 2026 May 26. pii: 176. [Epub ahead of print]45(6):
    Hormone-optimized hypocotyl-epicotyl-cotyledonary tri-complex explant system enables efficient soybean transformation with reduced genotype dependence.
    J Sushmitha, Durgeshwari Prabhakar Gadpayale, Navita Bansal, Ranjeet R Kumar, G Rama Prashat, Shivani Nagar, Soham Ray, Ashish Marathe, R Dinesh Kumar, Akshay Talukdar, Giriraj Kumawat, Viswanathan Chinnusamy, Suneha Goswami, T Vinutha.
       KEY MESSAGE: A composite hypocotyl-epicotyl-cotyledonary tri-complex (HECC) explant significantly improves soybean regeneration and Agrobacterium-mediated transformation efficiency (40.3%) while reducing genotype dependence, providing a rapid and robust platform for functional genomics. Soybean genetic transformation is hindered by low regeneration efficiency and considerable genotype dependency. Here, we present a hormone-optimized Agrobacterium-mediated transformation system employing a composite hypocotyl-epicotyl-cotyledonary tri-complex (HECC) explant that integrates multiple meristematic regions within a single explant and significantly improves regeneration and transformation efficiency. Compared to conventional single-meristem explant systems such as cotyledonary node and half-seed explants, HECC explants exhibited substantially higher regeneration frequencies and achieved an average transformation efficiency of 40.3%, calculated as the number of PCR-positive shoots obtained per infected explant in the JS-335 cultivar. Optimization of hormone combinations, particularly trans-zeatin riboside in shoot induction and elongation and indole-3-butyric acid (IBA) during rooting, promoted robust organogenic responses and reduced tissue damage. The system supported efficient transformation (26-41%) across multiple soybean cultivars, including JS-335, JS-2034, JS-2069 and PUSA-9712, indicating reduced genotype dependence compared with conventional explant systems. To demonstrate the applicability of this system for genome engineering, a CRISPR/Cas9 construct targeting GmSPL9c (Glycine max SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 9c), a transcription factor involved in regulating plant developmental transitions and shoot architecture, was introduced. Molecular analyses by PCR and qRT-PCR confirmed the integration and expression of cas9 and bar genes, while segregation analysis in T1 progeny demonstrated heritable transmission consistent with a 3:1 Mendelian segregation ratio. Functional selection by BASTA® spraying in the T1 generation further validated glufosinate tolerance and inheritance of the bar transgene. Collectively, this HECC-based system provides a reliable and reproducible platform for efficient soybean transformation and delivery of genome-editing constructs for functional genomics applications.
    Keywords:   Agrobacterium-mediated transformation; CRISPR/Cas9 ; HECC explant; Reduced genotype dependence; Regeneration frequency; Soybean; Stable integration
    DOI:  https://doi.org/10.1007/s00299-026-03803-y
  77. Methods Protoc. 2026 May 03. pii: 73. [Epub ahead of print]9(3):
    I-TEP: A Simple and Affordable Method to Measure Permeability in Reconstructed Tissues Combined with DAMO-TSC-Based Urea Assay.
    Yudaï Sahuc, Elissa Elia, Christophe Caneparo, Nathan Félix, Marilou Hardy, Stéphane Chabaud, Stéphane Bolduc.
      Trans-epithelial permeability is a critical functional parameter for reconstructed tissues, particularly in genitourinary tissue engineering, where urine leakage must be avoided. Although Franz diffusion cells are considered the gold standard for permeability measurements, their cost and limited accessibility restrict their widespread use. In parallel, the reliable quantification of urea in culture media remains challenging due to protein interference and assay cost. The Inexpensive Trans-Epithelial Permeability (I-TEP) test is a simple and a low-cost Franz-like permeability system which can be combined with an optimized diacetyl monoxime-thiosemicarbazide (DAMO-TSC) colorimetric urea assay. I-TEP system relies on readily available laboratory components to create physically separate donor and receiver compartments, with the tissue acting as the sole diffusion interface. The DAMO-TSC assay was optimized through systematic evaluation of deproteinization, incubation time, storage conditions, and serum interference. The I-TEP test showed a strong correlation with conventional Franz diffusion cells when testing similar tissue samples. Deproteinization was identified as a mandatory step for accurate urea quantification in serum-containing media. The combined approach was successfully applied on engineered genitourinary tissues, demonstrating sensitivity to tissue maturation and cellular composition. This protocol provides a proof of concept for an affordable, robust, and autonomous method for routine permeability assessment, bridging the gap between costly commercial systems and high-throughput experimental needs.
    Keywords:  permeation test; tissue engineering; urea dosage
    DOI:  https://doi.org/10.3390/mps9030073
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