bims-engexo Biomed News
on Engineered exosomes
Issue of 2026–07–05
72 papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Engineered immune cells and extracellular vesicles target tumour microenvironment barriers in solid tumour immunotherapy.
  2. The Dual Role of Exosomes in Gout: From Inflammatory Amplifiers to Therapeutic Regulators.
  3. Quercetin Delivered by Mesenchymal Stem Cell-Derived Exosomes Improves Liver Fibrosis via the PI3K/Akt Signaling Pathway.
  4. M1 macrophage-derived exosomal miR-155-5p exacerbates aortic dissection via SMAD5-Mediated regulation of vascular smooth muscle cell phenotype.
  5. Engineered extracellular vesicles for ischemic heart diseases: modification methods, targeted delivery strategies, and multi-modal therapies - A systematic review.
  6. Targeted Strategies of Adipose Stem Cells for Metabolic Diseases: Mechanisms and Clinical Translation Challenges.
  7. Sprayable bioadhesive microcarriers loaded with Tβ4-Engineered ADSC exosomes for diabetic wound healing.
  8. Engineered Young Brown Adipose Tissue-Derived Exosomes Alleviate Radiation-Induced Lung Injury by Promoting G Protein-Coupled Receptor 183 Ubiquitination.
  9. Plant-derived extracellular vesicles as bioactive nanoplatforms: Biogenesis, therapeutic evidence, and translational challenges.
  10. Non-coding RNA networks in metabolic dysfunction-associated steatotic liver disease: Mechanisms and therapeutic perspectives.
  11. Wedelactone-loaded exosomes for sepsis-induced liver injury: a novel therapeutic strategy.
  12. Dual-engineered extracellular vesicles enabling endothelial targeting and EphrinB2 delivery for pulp revascularization.
  13. Glycyrrhetinic Acid-Grafted Glycogen Nanoparticles Mediated Hepatic Delivery of Survivin Antisense Oligonucleotides for Liver Cancer-Targeted Gene Therapy.
  14. Bioengineering advances in pancreatic cancer organoids for reproducible tumor microenvironment modeling.
  15. Precision prebiotics: Engineering food-derived polysaccharides to target specific SCFA-producing taxa for neuroprotection via the microbiota-gut-brain axis.
  16. Mechanistic insights into the synaptic damage-repair and regeneration processes in neurodegenerative Alzheimer's disease: phytochemicals as neuroprotective agents.
  17. Targeted delivery of doxorubicin using RSV F-protein modified breast cancer-derived exosomes in breast cancer-bearing mice.
  18. Context-dependent miRNA regulation in intervertebral disc degeneration: an IDD-focused dynamic network framework for stage-specific therapeutics.
  19. TAM-targeted nanomedicine in cancer: biological basis, therapeutic strategies, and translational perspectives.
  20. Research Progress on Natural Products and Synergistic Nanostrategies for Targeting Ferroptosis in Osteosarcoma.
  21. Plant-derived extracellular vesicles for drug delivery: current and future.
  22. A flexibility-driven delivery strategy for cationic liposomes to enhance tumor penetration and promote membrane fusion-mediated cellular entry.
  23. Bone marrow mesenchymal stem cell-derived exosomes exert therapeutic effects on inflammatory bowel disease through miR-148a-3p/Ets-1-dependent inhibition of pyroptosis.
  24. Milk-derived extracellular vesicles loaded with miR-146a-5p as a novel therapeutic strategy for allergic airway inflammation.
  25. Arginine-substituted Mastoparan-C derivatives combat dual bacterial pathogens: in vitro mechanistic insights and in vivo efficacy in polymicrobial wounds.
  26. Engineered cell-biomimetic nanosystems for anti-inflammatory therapy: Targeting, neutralization and immunomodulation.
  27. Bioengineered JMJD3-PROTAC targeted epigenetic immunotherapy strategy for diabetic periodontitis.
  28. Treatment of Severe Periodontitis using Exosome-Mediated Combination Therapies: A Retrospective Cohort Study.
  29. Engineered extracellular vesicles for combinatorial cancer therapy and imaging.
  30. Bioinspired electrospun nanofibrous dressings loaded with Mentha-derived exosome-like vesicles for antibacterial and immunomodulatory burn healing.
  31. Engineered iMSCs delivering wild-type IL-2 achieve dose-sparing tumor control via CD25-dependent CD8+ T-cell activation.
  32. Extracellular Vesicles from Mesenchymal Stem Cells Alleviate Spinal Cord Injury via the miR-486-5p/PTEN/PI3K/AKT Pathway.
  33. Bovine Milk-Derived Extracellular Vesicles as Emerging Drug Delivery Platforms: Current Advances, Applications and Challenges.
  34. Collagenase-Coated Polymeric Drug/siRNA Nanoparticles Overcome ECM and Regulate Metabolic Reprogramming of Fibroblasts for Alleviating Pulmonary Fibrosis.
  35. Engineering spherical nucleic acids for precision cancer therapy: design strategies and medical applications.
  36. Engineering Modular Cargo Loading Strategies for Carboxysome-Derived Protein Particles.
  37. Biomimetic Nanogels Programmed for Irreversible-Electroporation-Primed Tumor Microenvironments to Elicit Durable Antitumor Immunity.
  38. An opposite pH-responsiveness "gating" strategy: Intelligent sporopollenin exine armor for targeted therapy of colitis.
  39. Self-synergizing mutual prodrug liposomes for targeted cancer therapy via redox-amplified Pin1 inhibition.
  40. Advancements in delivery systems for in vivo chimeric antigen receptor T-cell therapy in urological diseases.
  41. Donkey Milk Exosomes Protect Against Dextran Sulfate Sodium-Induced Colitis by Delivering Anti-Inflammatory miRNAs and Reshaping Gut Microbiota.
  42. Peptide coacervate-mediated siRNA delivery for dual PD-1/PD-L1 blockade to enhance colorectal cancer immunotherapy.
  43. Soluble PD-1 drives renal fibrosis in CKD by disrupting immune homeostasis: Therapeutic mitigation via a targeted sPD-1 sequestration strategy.
  44. The Role of Human Placental Mesenchymal Stem Cell Derived Exosomes in Wound Healing and Scar Therapy.
  45. SpyCatcher-Engineered Ferritin Nanocages Enable Dual-Receptor Targeting for Enhanced Glioma Therapy.
  46. Stepwise mitochondria-targeted photodynamic immunotherapy enabled by an outer membrane vesicles-based nanoplatform for synergistic tumor ablation and immune reprogramming.
  47. Protein engineering combined with combinatorial optimization of critical synthetase cluster for efficient production of 1-Deoxynojirimycin in B. amyloliquefaciens.
  48. Engineering Guide RNAs for CRISPR-Based Biosensors.
  49. A celastrol derivative-based multifunctional nanozyme for oxidative stress scavenging and lipid metabolism regulation in metabolic dysfunction-associated steatotic liver disease.
  50. Therapeutic Vaccines Based on Iron-Coordinated Metal-Phenolic Networks for Eradicating Drug-Resistant Staphylococcus aureus.
  51. The Preparation and Physicochemical Characterization of a Triple Synergistic Nanoplatform Designed for Targeted Subcutaneous Delivery of Sitagliptin with Potential for β-Cell Preservation.
  52. Engineering asymmetric solvation structures for synergistically boosted quasi-solid thermocells.
  53. Targeted attenuation of liver fibrosis using microbubble-enhanced protease-activated receptor 1 chimeric antigen receptor T cells.
  54. Engineering Escherichia coli to produce medium chain oleochemicals from C2 substrates.
  55. Galactosylated chitosan-functionalized liposome for targeted delivery of Coreopsis tinctoria flavonoids: Protective effect in acute liver injury.
  56. PEG-NH2-Modified Gold Nanoparticle Deliver miRNA-140 for Effective Treatment of Osteoarthritis.
  57. Neutrophil membrane-mediated biomimetic nanoparticle for co-delivery of icariin and siORMDL3 attenuates asthma exacerbated by respiratory syncytial virus.
  58. Bio-recruiting hydrogel targeting mitochondrial homeostasis under neutrophil extracellular traps for diabetic wound repair.
  59. Selective silencing of placental anti-angiogenic factors in invasive trophoblasts via membrane-fusion divalent siRNA delivery for preeclampsia therapy.
  60. Ultrasound targeted fatty acid nitroalkene-containing lipid nanoparticles attenuate inflammation and reverse myocardial fibrosis.
  61. Extracellular Vesicles in the Tumor Microenvironment: Diverse Origins, Multifaceted Functions, and Emerging Therapeutic Opportunities.
  62. Exosomes in Cutaneous Wound Healing and Facial Skin Regeneration: Clinical and Translational Perspectives.
  63. Expression-linked promoter selection (ELiPS) engineers short, strong ubiquitous promoters for gene therapy applications.
  64. Shattering the "golden armor": A natural supramolecular nanoplatform for optical virulence modulation and MRSA keratitis therapy.
  65. Exosomes from mesenchymal stem/stromal cells and their therapeutic role in osteoarthritic pain.
  66. Dual-functional Nanocarrier for Improved Immunochemotherapy of Acute Myeloid Leukemia.
  67. Spatiotemporal delivery of exosomes and alendronate orchestrates osteoblastic and osteoclastic activity for osteoporotic bone regeneration.
  68. Exosome therapy for flap and skin graft survival: A systematic review and meta-analysis of preclinical evidence.
  69. CD4 + T cell-derived exosomal miR-223-3p serves as a potential biomarker for systemic lupus erythematosus and attenuates lupus nephritis in NZBWF1/J mice.
  70. Dysregulated methylation‒ubiquitination crosstalk accelerates intervertebral disc degeneration via MED12 destabilization and cGAS/STING activation.
  71. Silicon-Xanthenium Scaffold for pH- and Far-Red Light Dual-Responsive Photocage.
  72. Exosome-Biomaterial Platforms for Diabetic Skin Infections: Microenvironment Remodeling, Responsive Delivery, and Clinical Translation.
  1. Discov Oncol. 2026 Jul 02.
    Engineered immune cells and extracellular vesicles target tumour microenvironment barriers in solid tumour immunotherapy.
    Xiaowei Zhou, Shixin Chen, Junbo Liang.
      Adoptive cell therapy (ACT) for solid tumours frequently fails because the tumour microenvironment (TME) imposes multiple, overlapping barriers, including stromal exclusion, suppressive myeloid networks, inhibitory cytokines and metabolites, and antigen heterogeneity. Collectively, these factors markedly restrict the infiltration, persistence, and cytotoxic function of effector lymphocytes. In this Review, we synthesise recent primary studies, consensus guidance, and clinical-trial evidence on engineered-cell therapies, including chimeric antigen receptor (CAR) T cells, T-cell receptor-engineered T cells (TCR-T cells), CAR-NK cells, CAR-macrophages (CAR-M), and emerging in vivo CAR-engineering strategies, together with extracellular-vesicle (EV)-based therapeutics. We then map each platform to mechanism-linked resistance nodes within the TME. For engineered cells, key design levers include context-restricted recognition to reduce on-target/off-tumour toxicity, resistance to dominant suppressive pathways such as TGF-β and adenosine signalling, improved trafficking and tissue penetration, and controllability through transient programming or pharmacological switches. For EVs, the main translational advantages include tissue penetration, modular surface engineering, cargo loading, and their acellular nature, which avoids risks related to in vivo cellular expansion but introduces distinct challenges such as rapid clearance, immunogenicity, batch heterogeneity, and uncertain potency assays. Early clinical data using KRAS G12D-targeting engineered exosomes in metastatic pancreatic cancer support the feasibility of this approach and suggest that EVs may also remodel the immune microenvironment, providing a rationale for combination strategies. We propose a barrier-matched framework in which engineered cells and extracellular vesicles are assigned as functionally orthogonal but complementary modules: engineered cells provide adaptive cytotoxicity, whereas EVs enable microenvironmental reconditioning. This framework may help guide rational combination strategies designed to systematically dismantle resistance in solid tumours.
    Keywords:  CAR-NK; CAR-T; CAR-macrophage; Engineered exosomes; Extracellular vesicles; Immunotherapy resistance; Solid tumours; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s12672-026-05523-x
  2. Inflammation. 2026 Jul 01.
    The Dual Role of Exosomes in Gout: From Inflammatory Amplifiers to Therapeutic Regulators.
    Xuege Gao, Jiawei Zhang, Xiaojuan Kong, Yanli Xue, Weimin Fan.
      Gout is a metabolic disorder where excessive MSU crystals are found in joints and adjacent tissues. When the crystals are deposited acutely, they typically trigger loud and uncontrollable local inflammation. As we know, the main goals of diagnosis and treatment of the disease are the reduction of serum uric acid levels and treatment of acute inflammation. Although these methods are useful, we are still facing many challenges: early risk detection, personalized treatment plan and management of comorbidities associated with gout. As nanoscale vesicles for intercellular communication, exosomes are also receiving much attention due to their possible roles in the regulation of inflammation, pathogenesis and progression. We review the functions of exosomes in gout. Various mechanisms are known that exosomes regulate gouty inflammation. When immune cells activate MSU crystals, they release exosomes carrying mature IL-1β, NLRP3 inflammatory components and pro-inflammatory miRNAs that induce local inflammation. Exosomes from mesenchymal cells or other cell types may have other functions, such as NLRP3 inhibition and M2-polarized macrophage transporting the inflammation and tissue repair. It was carried out on vesicles collected from blood, synovial fluid, urine of patients for clinical studies. These vesicles differ in size, protein and miRNA expression because of the different stages of gout and could be the disease indicator. Most studies are still preliminary, small sample size and non-standard detection and evaluation. To translate these results into practice, more extensive prospective clinical trials are needed. Native and engineered exosomes are promising anti-inflammatory agents, modulating the immune system and facilitating precise tissue repair. Exosomes likely link MSU crystal deposition, acute inflammation and systemic immune metabolic dysregulation. Identifying the specific cell locations involved in gout is important for developing diagnostic and therapeutic approach for gout at earlier stages.
    Keywords:  Biomarkers; Exosomes; Gout; Intercellular communication; NLRP3 inflammasome
    DOI:  https://doi.org/10.1007/s10753-026-02551-1
  3. ACS Omega. 2026 Jun 30. 11(25): 38017-38028
    Quercetin Delivered by Mesenchymal Stem Cell-Derived Exosomes Improves Liver Fibrosis via the PI3K/Akt Signaling Pathway.
    Dan Fang, Jing Zhang, Qingqing Zhao, Yuting Fan, Xiaojin Lin, Dan Liang, Lianjun Zhong, Yingchun Zhang, Simeng Yan, Tao Shen, Yingkun Meng, Xing Zhao, Shi Zuo.
      Liver fibrosis represents a critical stage in the progression of chronic liver diseases to cirrhosis and hepatocellular carcinoma; however, effective therapeutic options remain limited. Although quercetin, a natural flavonol, possesses potent antifibrotic properties, its clinical utility is severely hindered by poor aqueous solubility and low bioavailability. To address this limitation, we developed a nanoparticle-based drug delivery system using quercetin-loaded human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes (hUC-MSC-exo-Que). Leveraging the innate biocompatibility and targeting capability of exosomes, this strategy aims to improve the pharmacokinetic limitations of quercetin and amplify its therapeutic efficacy. Our results demonstrate that hUC-MSC-exo-Que significantly attenuates liver fibrosis in a carbon tetrachloride-induced mouse model, outperforming free quercetin at the equivalent dose. This enhanced efficacy is attributed to the superior inhibition of hepatic stellate cell activation, as confirmed by in vitro studies. The engineered exosomes exhibited a sustained drug release profile (up to 48 h) and maintained excellent stability for at least 1 week. Integrating network pharmacology with experimental validation, we identify the antifibrotic mechanism involving potent inhibition of the PI3K/Akt signaling pathway, with hUC-MSC-exo-Que achieving markedly greater pathway suppression than free quercetin. By successfully transforming a potent but poorly bioavailable phytochemical into a targeted nanotherapeutic, we present a promising preclinical strategy for liver fibrosis treatment and demonstrate a proof-of-concept platform for hydrophobic drug delivery.
    DOI:  https://doi.org/10.1021/acsomega.6c03434
  4. Bioact Mater. 2026 Nov;65 984-1004
    M1 macrophage-derived exosomal miR-155-5p exacerbates aortic dissection via SMAD5-Mediated regulation of vascular smooth muscle cell phenotype.
    Dengwei Cao, Xinyi Li, Shaoping Zhu, Jianfeng Chen, Haoxiang Li, Jiajun Shi, Xiaoqi Xiong, Jiahui Liu, Yumou Wang, Zhe Dong, Jiangping Song, Jinping Liu.
      Aortic dissection (AD) is a life-threatening cardiovascular emergency characterized by acute aortic wall injury and high mortality, yet effective pharmacological therapies remain limited. Macrophage infiltration and vascular smooth muscle cell (VSMC) phenotypic switching from contractile to synthetic states are central to AD pathogenesis, but the mechanisms mediating intercellular communication between macrophages and VSMCs are incompletely understood. Emerging evidence suggests that exosomes can transfer bioactive miRNAs between cells; however, whether M1 macrophage-derived exosomes promote AD progression through specific miRNA delivery and whether they can be engineered for therapeutic intervention have not been clearly defined. In this study, we demonstrate that M1 macrophage-derived exosomes deliver miR-155-5p to VSMCs, where it targets and suppresses SMAD5, activates the RHOA/ROCK pathway, and drives contractile-to-synthetic phenotypic switching, thereby accelerating AD progression. Through comprehensive physicochemical characterization, including TEM, NTA, Zeta potential, and stability assays, we show that M0 macrophage-derived exosomes can be successfully engineered to load Antago-miR-155-5p via electroporation with favorable encapsulation efficiency and colloidal stability. In a BAPN-induced mouse model of AD, intravenous administration of Antago-miR-155-5p-loaded M0-Exos significantly improved survival, reduced AD incidence and aortic dilation, and restored VSMC contractile markers. Biodistribution studies using DiR and CY5 labeling confirmed efficient accumulation of these engineered exosomes in the injured aorta, while macrophage depletion and rescue experiments validated the pathogenic role of M1-derived exosomes. These findings identify a novel M1 exosome-miR-155-5p-SMAD5/RHOA/ROCK signaling axis in AD and establish engineered M0 macrophage-derived exosomes as a promising bioactive material platform for targeted miRNA therapy in aortic dissection.
    Keywords:  Aortic dissection; Bioactive material; Exosomes; SMAD5; Targeted delivery; VSMC phenotypic switching; miR-155-5p
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.057
  5. Front Cardiovasc Med. 2026 ;13 1868328
    Engineered extracellular vesicles for ischemic heart diseases: modification methods, targeted delivery strategies, and multi-modal therapies - A systematic review.
    Sha Su, Yu Teng, Shaojiao Liu, Lei Wang, Mingjing Zhao.
       Background/purpose: Due to the complex pathological process of ischemic heart diseases (IHD), a single treatment strategy had limited efficacy. Multi-targeted synergy, precise delivery, and long-lasting effects were new directions for treatment. Engineering extracellular vesicles (EVs) had become a research hotspot in the field of IHD treatment due to their ability carrying therapeutic signaling molecules, precise tissue targeting capabilities, and excellent biocompatibilities. This systematic review focused on the modification methods, targeting strategies, and combined effects of multi-pathway synergy of engineered EVs in IHD treatment.
    Methods: Systematic searches were conducted in 8 databases. According to strict inclusion and exclusion criteria, the literature was screened, and relevant information was extracted based on the research purpose. Two researchers independently screened the literature, extracted information, and evaluated the quality of literatures.
    Results: A total of 50 animal studies were included. The existing studies mainly achieved the engineering modification of EVs through internal loading/knockdown, surface modification, membrane fusion, combination with biotechnological materials, and pre-treatment; and by using targeting peptides or specific antibodies modification, membrane fusion, and in situ cardiac delivery, to enhance their targeting enrichment abilities for ischemic myocardium. In terms of therapeutic effects, engineered EVs could exert beneficial effects on cardiac function through multiple pathways, such as alleviating myocardial fibrosis, inhibiting inflammatory responses, promoting angiogenesis, reducing cardiomyocyte apoptosis, and improving mitochondrial metabolism. The multi-modal therapy of engineered EVs presented a pyramid structure: improving cardiac function served as the foundation, ameliorating classical cardioprotective pathways constituted the primary pillars, and optimizing metabolic modulation represented supplementary.
    Conclusion: There was an intrinsic association between the multi-association therapeutic effects of engineered EVs and the modification methods. Currently, the modification strategies of engineered EVs formed a composite system of " internal cargo loading/knockdown of core signaling molecules + surface modification and membrane fusion to enhance targeting specificity + combination with bioengineering materials for local sustained release", which met the multiple needs of multi-targeted synergy, precise delivery, and long-lasting effects. This systematic review provided key theoretical basis and practical guidance for constructing a multifunctional EVs delivery system for treating IHD and accelerating its clinical translation and application.Systematic Review Registration: https://www.crd.york.ac.uk/, identifier PROSPERO CRD420261393475.
    Keywords:  IHD; engineered extracellular vesicles (engineered EVs); extracellular vesicles (EVs); multi-modal therapy; targeting strategy
    DOI:  https://doi.org/10.3389/fcvm.2026.1868328
  6. Stem Cell Rev Rep. 2026 Jun 30.
    Targeted Strategies of Adipose Stem Cells for Metabolic Diseases: Mechanisms and Clinical Translation Challenges.
    Menghan Chen, Siqi Ding, Wanying Chen, Yanming Chen, Liqun Li, Yucang He, Hao Dai.
      Metabolic diseases, such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and atherosclerosis, represent a growing global health burden. Adipose-derived stem cells (ADSCs) have emerged as promising therapeutic agents due to their multipotency, paracrine activity, and potential for engineering targeted interventions. This review highlights recent advances in targeted ADSC strategies, focusing on their mechanisms, clinical applications, and translational challenges. Key targeted approaches include engineered exosomes for precise immunomodulation, surface-modified ADSCs for enhanced tissue homing, and biomaterial-based delivery systems for sustained and local release. Preclinical studies have demonstrated that these strategies can significantly improve glucose homeostasis, reduce hepatic steatosis, and alleviate chronic inflammation. However, clinical translation faces hurdles, including donor-dependent heterogeneity, a lack of standardized protocols, and insufficient long-term safety data. Future efforts should prioritize the development of precision-targeted ADSC therapies through genetic engineering, functionalized biomaterials, and rigorously controlled clinical trials to fully exploit their potential to treat metabolic diseases.BackgroundMetabolic diseases are prevalent worldwide, with conditions such as metabolic dysfunction-associated steatotic liver disease(MASLD), obesity, type 2 diabetes mellitus, and atherosclerosis affecting hundreds of millions of individuals. Existing therapies struggle to address the root causes of these conditions, creating an urgent clinical need. ADSCs have gained attention as a research hotspot due to their multifunctionality; however, the literature indicates that their clinical translation faces obstacles, including cellular heterogeneity, the absence of standardized protocols, and unresolved safety concerns. This review aims to review and summarize the research progress on targeted ADSC strategies for metabolic diseases, clarify their mechanisms of action, review preclinical and clinical evidence, and provide directions to overcome translational bottlenecks.
    Keywords:  Adipose-derived stem cells; Cellular heterogeneity; Clinical translation; Metabolic diseases; Therapeutic mechanism
    DOI:  https://doi.org/10.1007/s12015-026-11186-6
  7. Bioact Mater. 2026 Nov;65 845-859
    Sprayable bioadhesive microcarriers loaded with Tβ4-Engineered ADSC exosomes for diabetic wound healing.
    Youjun Ding, Danqing Huang, Zhiwei Zhao, Han Feng, Shuyin Zhou, Danni Qian, Yepeng Zhang, Yuanjin Zhao, Min Zhou.
      Stem cell-derived therapeutics show strong potential to recalibrate diabetic wound immunity, yet their stability, retention, and practical usability remain major barriers to effective application. Here, we report a novel microcarrier platform loaded with thymosin β4 (Tβ4)-overexpressing stem cell-derived exosomes for a sprayable diabetic wound dressing. Adipose-derived stem cells (ADSCs) were genetically engineered to overexpress Tβ4, generating potent immunoregulatory exosomes that were efficiently encapsulated into uniform, micron-scale hydrogel microcarriers via microfluidic fabrication and further functionalized with a mesoporous polydopamine (mPDA) coating to enhance wet adhesion and tissue retention. The resulting EXOsTβ4/mPDA@MS system stabilizes the exosome payload and enables convenient spray-based wound administration. These microcarriers provide sustained, localized exosome release, significantly enhance macrophage efferocytosis, suppress inflammatory signaling, and accelerate wound repair in diabetic models. Thus, our engineered, sprayable, and adhesive microcarrier platform offers a stable, minimally invasive, and clinically adaptable strategy for advancing stem cell-derived exosome therapies in chronic diabetic wound repair.
    Keywords:  Efferocytosis; Microcarrier; Polydopamine; Stem cell; Thymosin β4
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.06.024
  8. ACS Nano. 2026 Jul 02.
    Engineered Young Brown Adipose Tissue-Derived Exosomes Alleviate Radiation-Induced Lung Injury by Promoting G Protein-Coupled Receptor 183 Ubiquitination.
    Hua Guan, Jingjing Yang, Yang Han, Huiji Pan, Jinhua Luo, Yongyi Wang, Benyang Li, Ruixue Huang.
      Acute radiation-induced lung injury is a serious and potentially life-threatening complication of radiotherapy for thoracic malignancies or accidental radiation exposure, characterized by high incidence, limited treatment options, and substantial mortality. To address the lack of effective therapies for preventing and treating radiation-induced lung injury, we developed an engineered nanoplatform, BAT-exo@Au, generated by functionalizing exosomes derived from young brown adipose tissue (BAT) with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-thiol (DSPE-PEG-SH) and gold nanoparticles via chloroauric acid (HAuCl4) incubation. Our results show that BAT-exo@Au was efficiently internalized by irradiated lung tissue and exerted radioprotective effects by suppressing reactive oxygen species production and attenuating radiation-induced inflammatory responses. In addition, BAT-exo@Au mitigated radiation-induced epithelial-mesenchymal transition while enhancing tumor radiosensitivity, suggesting a dual therapeutic advantage. Mechanistically, BAT-exo@Au reduced apoptosis and preserved mitochondrial membrane potential after radiation in vitro. Transcriptomic analysis identified G protein-coupled receptor 183 (Gpr183) as a potential downstream target, showing upregulation after radiation but downregulation following BAT-exo@Au treatment. Further in vitro experiments demonstrated that BAT-exo@Au promoted the interaction between Gpr183 and the E3 ubiquitin ligase NEDD4, facilitating Gpr183 ubiquitination and proteasomal degradation. This study suggests that exosomes derived from young BAT may serve as a therapeutic strategy for the prevention of radiation-induced lung injury. In conclusion, BAT-exo@Au shows promise as a preventive approach for radiation-induced lung injury, potentially through modulation of Gpr183 via enhanced Gpr183-NEDD4 interaction and ubiquitination.
    Keywords:  Engineered exosomes; Lung injury; Radiation; Ubiquitination; Young brown adipose tissue
    DOI:  https://doi.org/10.1021/acsnano.6c05744
  9. Biochem Biophys Rep. 2026 Sep;47 102688
    Plant-derived extracellular vesicles as bioactive nanoplatforms: Biogenesis, therapeutic evidence, and translational challenges.
    Jingcheng Yu, Yuren Shen, Hao Jia.
       Background: Plant-derived extracellular vesicles (PDEVs) are nanoscale membrane vesicles isolated from edible or medicinal plants. They have attracted interest because they combine endogenous biological activity with the practical advantages of scalable natural nanocarriers.
    Objective: This mini-review examines PDEVs from a pharmaceutical development perspective rather than as a broad catalogue of biological observations. We focus on how vesicle source, isolation workflow, cargo composition, and route of administration affect therapeutic interpretation and translational feasibility.
    Content: We summarize PDEV biogenesis, isolation, characterization, and interaction with mammalian cells, and compare PDEVs with mammalian exosomes and synthetic liposomes. Representative preclinical studies in bone repair, neurological injury, inflammatory and gastrointestinal disease, cancer, and renal stone disease are critically evaluated, with attention to dose heterogeneity, model limitations, and mechanistic strength. We also discuss PDEVs as engineered carriers for exogenous therapeutics and revisit the debate around dietary plant miRNA uptake and cross-kingdom regulation.
    Conclusion: PDEVs offer several practical advantages, including oral compatibility, scalable sourcing, and potential dual use as intrinsic therapeutics and delivery systems. The field remains limited by inconsistent terminology, non-standardized purification, incomplete pharmacokinetic profiling, and scarce clinical data. Future translation will require rigorous quality control, reproducible potency assays, comprehensive biodistribution studies, and clear regulatory positioning.
    Keywords:  Cross-kingdom communication; Oral nanocarriers; Pharmaceutical design; Plant-derived extracellular vesicles; Plant-derived nanovesicles; Therapeutic translation
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102688
  10. Liver Res. 2026 Jun;10(2): 151-165
    Non-coding RNA networks in metabolic dysfunction-associated steatotic liver disease: Mechanisms and therapeutic perspectives.
    Ruizhe Ren, Siying Ren, Yihan Xu, Xiao Liang, Xiyang Wei.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disorder worldwide, characterized by complex molecular regulatory networks driving its pathogenesis. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), serve as critical regulators of gene expression and have been increasingly recognized for their pivotal roles in MASLD development. Rather than functioning in isolation, these ncRNAs form intricate regulatory networks that integrate and amplify disease signals across multiple cellular compartments and pathological stages. This review provides a comprehensive overview of how these ncRNA networks orchestrate MASLD progression, focusing on their roles in metabolic dysregulation, inflammation, and fibrosis. We further evaluate the diagnostic potential of circulating ncRNAs as stable, non-invasive biomarkers for disease stratification and monitoring, and discuss emerging therapeutic strategies targeting ncRNAs, including antisense oligonucleotides, synthetic mimics, and advanced delivery platforms such as lipid nanoparticles and engineered exosomes. Despite significant progress, challenges related to delivery efficiency, tissue specificity, and safety remain barriers to clinical translation. By synthesizing current knowledge of ncRNA networks in MASLD and highlighting opportunities for therapeutic intervention, this review provides a roadmap for translating ncRNAs into clinical applications for this increasingly prevalent metabolic liver disease.
    Keywords:  Biomarkers; Metabolic dysfunction-associated steatotic liver disease (MASLD); Non-coding RNAs (ncRNAs); Regulatory networks; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.livres.2026.05.002
  11. Drug Deliv. 2026 Dec 31. 33(1): 2693353
    Wedelactone-loaded exosomes for sepsis-induced liver injury: a novel therapeutic strategy.
    Yanping Yin, Lulu Zhang, Yanli Yin, Jinyi Zhao, Rui Gong, Xuan Zhou, Haiyue Zhang, Fei Mu, Jingwen Wang.
      Sepsis-induced liver injury (SILI) is an important cause of death in intensive care patients, which seriously affects clinical prognosis. Wedelolactone (WEL) exhibits hepatoprotective properties, however, its clinical application is constrained by its poor solubility and insufficient targeting ability. Therefore, in this study, an innovative exosome (Exo)-based drug delivery system loaded with WEL (Exo@WEL) was constructed. The aim was to enhance the liver-targeting efficacy and therapeutic performance of WEL. Exo were extracted from the mice macrophages cell line RAW264.7 by differential centrifugation, and WEL was successfully loaded using ultrasonic incubation. Exo@WEL was characterized by TEM, particle size analysis, and NTA, confirming its structural suitability as an exogenous agent. DiR labeling revealed that Exo@WEL had a significantly enhanced liver-targeting ability compared to WEL. Safety was confirmed by HE staining test. In the SILI models, Exo@WEL showed better hepatoprotection over WEL. Beyond entinfinmtory actvity menifested y decreased ro infammatory rokines, Exo@WEL reinforced antioxidant function and efectively restained feroptosis. Importantly, pharmacological inhibition of ML385, a selective Nrf2 inhibitor, confirmed the critical regulatory role of the Nrf2 pathway in mediating these multifaceted liver protective effects. This study pioneered the development of a targeted Exo-based nanoplatform (Exo@WEL) for SILI therapy. The mechanism study has revealed a potential therapeutic strategy for inhibiting oxidative stress and ferroptosis by regulating the Nrf2/SLC7A11/GPX4 axis. This preparation provides a novel nanotherapeutic strategy that combines high efficiency and safety for the treatment of SILI. These findings also lay a theoretical foundation for the clinical translation of Exo drug delivery systems.
    Keywords:  Sepsis-induced liver injury; exosome; ferroptosis; oxidative stress; wedelactone
    DOI:  https://doi.org/10.1080/10717544.2026.2693353
  12. J Nanobiotechnology. 2026 Jun 30.
    Dual-engineered extracellular vesicles enabling endothelial targeting and EphrinB2 delivery for pulp revascularization.
    Anqi Liu, Mengying Li, Peiyu Tang, Weiwen Ge, Zhengliang Han, Yige Dai, Lei Zhang, Changyong Yuan, Lei Qi.
      Dental pulp pathologies impair quality of life and systemic health. Obstacles to revascularization remain a key challenge in regenerating dental pulp tissue. To address these challenges, dual-engineered extracellular vesicles (EVs) were developed, incorporating EphrinB2 as a pro-regenerative payload alongside the DNA aptamer Apt02 for endothelial-targeting specificity. This study identified 1 µg/mL as the optimal concentration for fabricating EphrinB2-loaded extracellular vesicles (B2-EVs). At this concentration, B2-EVs significantly enhanced the proliferation, migration, and capillary morphogenesis of HUVECs. Subsequent integration of the endothelial-targeting Apt02 yielded Apt-B2-EVs, which demonstrated superior affinity for HUVECs and amplified pro-angiogenic capacity. Mechanistic analyses confirmed that Apt-B2-EVs promote angiogenesis via the EphrinB2/EphB4-dependent Akt/ERK signaling cascade. These vesicles were further encapsulated within methacrylated gelatin (GelMA) hydrogel, exhibiting sustained release kinetics and excellent biocompatibility. Implantation of Apt-B2-EVs@GelMA into root canals established pulp organoids, which, upon ectopic transplantation in nude mice, robustly enhanced vascularization. The dual-engineered Apt-B2-EVs present a potent strategy for recruiting endothelial cells and delivering EphrinB2 to enable functional pulp revascularization within root canal niches, laying a translational foundation for next-generation functional pulp regeneration.
    Keywords:  Apt02-targeted delivery; Engineered extracellular vesicles; EphrinB2; Pulp revascularization
    DOI:  https://doi.org/10.1186/s12951-026-04736-0
  13. ACS Omega. 2026 Jun 30. 11(25): 37102-37112
    Glycyrrhetinic Acid-Grafted Glycogen Nanoparticles Mediated Hepatic Delivery of Survivin Antisense Oligonucleotides for Liver Cancer-Targeted Gene Therapy.
    Huijie Zhang, Shiying Li, Ruixuan Cui, Xin He, Sijie Liu, Fanxi Yin, Yan Zhang.
      As an apoptosis inhibitor, survivin has become a highly promising cancer target due to its overexpression in most tumors and its near absence in normal tissues. While antisense oligonucleotides (ASOs) targeting survivin mRNA represent a promising therapeutic approach for liver cancer, their clinical translation is significantly hampered by critical challenges such as rapid enzymatic degradation, poor cellular internalization, and off-target tissue distribution. Although strategies such as chemical modification of ASO and the use of synthetic nanocarriers show promise, they also raise safety issues. Effectively delivering ASO into tumor cells still poses a significant challenge. Herein, we engineered an innovative glyco-nanovector aimed at the hepatic delivery of survivin ASO, with the goal of advancing gene therapy strategies for liver cancer. Glycogen was first aminated (NG) and subsequently chemically modified with glycyrrhetinic acid (GA). GA is a ligand targeting the GA receptors that are overexpressed in hepatocellular carcinoma (HCC) cells, and it also exhibits anticancer effects against HCC. The resulting GA-NG exhibited excellent biocompatibility. GA-NG formed stable complexes with survivin ASO and effectively shielded them from nuclease degradation. Moreover, GA modification enabled the GA-NG to significantly enhance the cellular uptake of survivin ASO in HepG2 cells through GA receptor-mediated endocytosis, thereby potentiating apoptotic cell death. The GA-NG/ASO effectively suppressed tumor growth by downregulating survivin expression, demonstrating potent gene silencing efficacy with no systemic toxicity. This work highlights the promising potential of GA-NG/ASO for targeted gene therapy against hepatocellular carcinoma.
    DOI:  https://doi.org/10.1021/acsomega.6c01297
  14. iScience. 2026 Jul 17. 29(7): 116487
    Bioengineering advances in pancreatic cancer organoids for reproducible tumor microenvironment modeling.
    Renyu Chen, Bohui Yin, Yaowei Zhang, Junya Peng, Xiaoliang Guo, Wenming Wu.
      Pancreatic ductal adenocarcinoma (PDAC) remains lethal due to late-stage diagnosis and limited non-surgical treatment options. Its intratumoral heterogeneity and desmoplastic tumor microenvironment (TME) drive invasion, immune escape, and treatment failure. Patient-derived organoids (PDOs) have emerged as efficient model platforms for simulating the TME and preserving tumor heterogeneity and enabling functional testing in vitro; however, conventional PDO cultures lack defined and controllable microenvironmental components and often exhibited limited reproducibility, physiological fidelity, and observability. This review synthesizes recent bioengineering advances that upgrade pancreatic cancer PDO platforms across three interconnected dimensions: (1) engineered extracellular matrices and biofabrication for reproducible construction; (2) co-culture, microfluidic, and bioreactor systems for physiological fidelity; (3) imaging AI and biosensor pipelines for quantitative monitoring. We highlight practical design principles and remaining bottlenecks for standardization, scalability, and clinical translation.
    Keywords:  bioengineering; biological sciences; cancer
    DOI:  https://doi.org/10.1016/j.isci.2026.116487
  15. Curr Res Food Sci. 2026 ;13 101471
    Precision prebiotics: Engineering food-derived polysaccharides to target specific SCFA-producing taxa for neuroprotection via the microbiota-gut-brain axis.
    Yanmei Yin, Yugang Li, Xiaobin Zhang, Mengwei Jia, Shu Zhu, Chengcheng Liu.
      Neurodegenerative and neuropsychiatric disorders lack disease-modifying therapies. The microbiota-gut-brain (MGB) axis, particularly short-chain fatty acid (SCFA)-producing microbiota dysbiosis, has emerged as a conserved driver of neuroinjury pathogenesis. Natural food-derived polysaccharides have been explored as prebiotic substrates, but their clinical translation is hindered by poor target specificity, high interindividual heterogeneity, and low bioavailability. Engineered food-derived polysaccharides, as a next-generation precision prebiotic platform, enable rational tailoring of molecular fine structures via targeted physical, chemical, biological, and combinatorial modification technologies, aiming for strain-specific directional modulation of intestinal SCFA-producing microbiota and multi-pathway neuroprotection through the MGB axis. In this review, we systematically delineate the bidirectional regulatory mechanisms between SCFA-producing microbiota and neural homeostasis, dissect disease-specific pathological cascades driven by SCFA-producing microbiota dysbiosis, and discuss conflicting findings on the dual effects of SCFAs. We further propose a full-chain framework of the structure-activity relationship of engineered polysaccharides, dissecting core modification strategies, strain-specific targeting mechanisms, and a multi-dimensional efficacy evaluation system for these precision prebiotics. Additionally, we assess safety evaluation status, major global regulatory differences, and core clinical translation bottlenecks. Finally, we outline key unresolved challenges and propose a conceptual roadmap for AI-assisted rational design of precision prebiotics, personalized microbiota-adapted intervention strategies, and multicenter clinical translation directions. This review provides a mechanism-driven theoretical framework and practical guidance for developing engineered food-derived polysaccharides as precision nutrition interventions for neuroinjury-related disorders.
    Keywords:  Food polysaccharides; Gut microbiota; Gut-brain axis; Neuroprotection; Precision prebiotics; Short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.crfs.2026.101471
  16. Front Synaptic Neurosci. 2026 ;18 1835778
    Mechanistic insights into the synaptic damage-repair and regeneration processes in neurodegenerative Alzheimer's disease: phytochemicals as neuroprotective agents.
    Bharti Yadav, Prabhakar Gangwar, Kirti Kumari, Anuradha Yadav, Rashmi Rao, Keshav Kumar, Harkomal Verma, Monisha Dhiman, Anil Kumar Mantha.
      Synaptic failure is one of the earliest and most significant contributors to the cognitive decline in Alzheimer's disease (AD), preceding extensive neuronal loss. Although amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein characterize the disease, memory impairment primarily results from the gradual deterioration of synaptic communications. This decline is caused by a complex interaction among mitochondrial energy deficits, cytoskeletal instability, disrupted exosomal signaling, and immune-mediated synaptic pruning. Mitochondrial dysfunction, particularly affecting complexes I and IV, leads to reduced ATP production, faulty mitophagy and disrupted calcium (Ca2+) homeostasis, placing the synapse under constant metabolic stress. Elevated reactive oxygen species (ROS) further activate stress pathways, including p38 MAPK and JNK, contributing to synaptic protein damage and impaired long-term potentiation (LTP). Furthermore, tau hyperphosphorylation destabilizes the neuronal cytoskeleton, weakening dendritic spine integrity and synaptic connectivity. At the same time, Aβ alters the cargo carried by exosomes, facilitating the spread of pathogenic Aβ and tau species between the neurons and modulating microglial activation and complement-mediated synaptic pruning. Additionally, emerging studies highlight the role of NETosis in exacerbating neuroinflammation and compromising the blood-brain barrier (BBB) integrity, thereby increasing synaptic damage. In contrast, phytochemicals such as resveratrol, ginkgolide B, curcumin, ferulic acid, epigallocatechin gallate (EGCG), and quercetin exert neuroprotection by restoring redox balance, altering exosomal communications, stabilizing cytoskeletal signaling, and reducing neuroinflammation. Moreover, delivery techniques such as nanoparticles and engineered exosomes enhance BBB permeability and enable targeted synaptic intervention. Overall, this review summarizes current mechanistic findings and highlights the potential of phytochemicals as multitarget therapeutic agents for synaptic repair and functional recovery in AD.
    Keywords:  Alzheimer’s disease; NETosis; cytoskeleton; exosomes; mitochondrial dysfunction; phytochemicals; synaptic plasticity
    DOI:  https://doi.org/10.3389/fnsyn.2026.1835778
  17. Bioimpacts. 2026 ;16 33180
    Targeted delivery of doxorubicin using RSV F-protein modified breast cancer-derived exosomes in breast cancer-bearing mice.
    Narges Mardi, Amir Zarebkohan, Cigir Biray-Avci, Reza Rahbarghazi, Mehdi Talebi, Hamid Lotfimehr, Sharareh Khavandkari, Zahra Abbasi-Malati, Nastaran Sedghi-Samarkhazan, Elham Shahriyari, Asghar Khalilnezhad, Morteza Milani, Mohammad Nouri.
       Introduction: Triple-negative breast cancer demonstrated high metastasis and mortality rates in female populations. Emerging data on effective targeting and specific internalization of chemotherapeutic agents, using modified exosomes, decreased the therapeutic dosage of anti-cancer drugs in cancer cells.
    Methods: Herein, we developed modified exosomes by surface decoration using the Fusion protein of Respiratory Syncytial Virus (F-protein of RSV) through Click-chemistry techniques, and Dox-loaded via sonication strategy. Then, the viability and metastatic behaviors of MDA-MB-231 cells were monitored in the presence of different groups, including Dox, Exosomes (Exo), Exosomes loaded with Dox (Exo@Dox), and F-protein coupled Exosome groups (Exo-F) and (Exo-F@Dox).
    Results: In vitro and in vivo results verified that the F-protein coupled exosome, as a modified natural nanoplatform, possessed a biocompatible nature in blood circulation and crossing of blood barriers. After exposure to tumoral temperature (40 °C) and lysosomal PH (5.5) demonstrate amplified Dox release (around 60% at 8 h). Also, in vitro uptake results confirmed a significant increase in Exo-F internalization compared to the Exo group in MDA-MB-231 cells (P<0.0001). Correspondingly, the IC50 value of Exo-F@Dox versus free Dox showed a significant reduction (24-fold more potent) (P<0.0001). Interestingly, Dox-free modified Exo (Exo-F) showed appreciable cytotoxicity (IC50 of about 0.1 µg /mL for exosomal protein concentration) (P˂0.0001). Also, migration assay results confirmed a considerable decrease in the migrated population of MDA-MB-231 cells (10%) compared to the control group, following exposure to modified exosomes. Interestingly, an in vivo study in tumor-bearing Balb/c mice demonstrated a significantly decreased tumor size in the Exo-F groups compared to other formulations.
    Conclusion: In summary, F-protein modified exosomes exhibited superior anticancer efficacy by improving tumor-specific targeting, ensuring precise delivery of chemotherapeutic agents, facilitating efficient drug release, and allowing for lower therapeutic dosages.
    Keywords:  Breast cancer; Fusion protein of RSV; Modified exosomes; Targeted delivery
    DOI:  https://doi.org/10.34172/bi.33180
  18. Front Cell Dev Biol. 2026 ;14 1844246
    Context-dependent miRNA regulation in intervertebral disc degeneration: an IDD-focused dynamic network framework for stage-specific therapeutics.
    Yanchao Gu, Ling Zhu, Wang Chen, Xianghu Zhao, Zhanghua Li.
      Intervertebral disc degeneration (IDD) is a progressive, mechanically regulated, and inflammation-associated disease in which microRNAs (miRNAs) participate in extracellular matrix remodeling, cell death, inflammatory signaling, and intercellular communication. However, the reported functions of individual miRNAs in IDD are often inconsistent across studies, with the same miRNA being associated with protective, neutral, or pro-degenerative outcomes under different experimental or pathological conditions. This inconsistency highlights a central knowledge gap: whether miRNA function in IDD is determined primarily by intrinsic molecular identity or by the dynamic pathological context in which the miRNA is embedded. In this Hypothesis and Theory article, we propose the Context-Dependent miRNA Switching Model (CDMSM), an IDD-focused conceptual framework in which degeneration stage, mechanical loading, inflammatory intensity, oxidative stress, extracellular matrix status, and ceRNA-network remodeling jointly reshape miRNA-target interactions and thereby alter biological output. The model predicts that selected miRNAs may display stage-dependent target bias, altered effective concentration due to ceRNA competition, and different therapeutic effects across early, intermediate, and chronic/late-stage IDD. We further discuss how CDMSM may guide stage-specific miRNA therapeutics, including engineered exosomes, miRNA inhibitors, and microenvironment-responsive biomaterials. Finally, we outline experimental strategies required to test the model, including longitudinal animal models, controlled mechanobiology systems, single-cell and spatial transcriptomics, and functional perturbation of miRNA-target networks.
    Keywords:  ceRNA network; context-dependent regulation; engineered exosomes; intervertebral disc degeneration; low back pain; mechanobiology; microRNA
    DOI:  https://doi.org/10.3389/fcell.2026.1844246
  19. Theranostics. 2026 ;16(13): 7537-7570
    TAM-targeted nanomedicine in cancer: biological basis, therapeutic strategies, and translational perspectives.
    Lili Zhou, Fang Yuan, Yangyang Wu, Xin Li, Debiao Xiang.
      Tumor-associated macrophages (TAMs) are the most common immune cell type found in the tumor microenvironment. They are also key participants in the regulation of angiogenesis, metastasis, immune evasion, and therapeutic resistance. Recent single-cell transcriptomics and spatial profiling have shown that TAMs are extremely heterogeneous and functionally plastic beyond the traditional M1/M2 paradigm, and that more refined therapeutic strategies are required. Nanomedicine can integrate macrophage biology, the tumor microenvironment, and the engineering of the delivery system to design TAM-oriented interventions. With optimization of delivery systems (e.g. particle size, surface chemistry, ligands, therapeutic payloads, and the type of stimuli), multiple functionalities can be engineered to improve macrophage (in the tumor microenvironment) recruitment, depletion, reprogramming, and enhancement of TAM phagocytosis, antigen presentation, and immune regulation. Nanoparticles with biomimetic systems, macrophage membrane coating, as well as macrophage-derived extracellular vesicles and engineered exosome platforms, can also provide a wide array of options for TAM-oriented therapy. In this review, we provide an overview of the origin, heterogeneity, and functions of TAMs in cancer, and categorize TAM-targeted nanotherapeutics based on the principal approaches of recruitment blockade, tumor-promoting macrophage depletion, reprogramming, functional enhancement of phagocytosis and immune activation, and biomimetic drug delivery. We also present a comparison of representative nanoplatforms, highlight the latest clinical developments, and investigate key barriers to moving research from the lab to the clinic using nanomedicine, including delivery system design focused on targeting TAMs, safe and effective delivery to tumors, off-target effects on macrophages, ease of manufacture, and control of product quality. By combining TAM biology with the design of specialized nanocarriers and clinical research, this review outlines the main directions of research and provides a practical approach to the development of specialized TAM-targeted cancer nanomedicines.
    Keywords:  biomimetic drug delivery; clinical translation; macrophage reprogramming; nanomedicine; tumor-associated macrophages
    DOI:  https://doi.org/10.7150/thno.132714
  20. Curr Med Chem. 2026 Jun 24.
    Research Progress on Natural Products and Synergistic Nanostrategies for Targeting Ferroptosis in Osteosarcoma.
    Chao Chen, Qianlin Zuo, Qicong He, Zijiu Yangyang, Guishuai Wu, Haoyan Luo, Xingguo Li, Fan Zhang.
      Emerging evidence suggests that ferroptosis, a unique iron-dependent form of regulated cell death driven by lipid peroxidation and morphologically distinct from apoptosis or necrosis, plays a vital role in the pathophysiological progression and therapy resistance of osteosarcoma (OS). Accumulating evidence supports ferroptosis induction as a critical therapeutic strategy for OS, and pharmacological activation of ferroptosis by natural products represents a promising target for combating this malignancy. In this review, the core mechanisms of ferroptosis (including dysregulated iron/lipid/amino acid metabolism and autophagy-mediated regulation) and their roles in OS pathogenesis and chemoresistance are systematically described. Finally, emerging findings in treating OS through pharmacological induction of ferroptosis by bioactive natural compounds (e.g., flavonoids, curcuminoids, and terpenoids), functional nanomaterials (e.g., targeted drugloaded nanoparticles and GSH-depleting agents), and engineered exosomes are comprehensively summarized. Collectively, available evidence-predominantly from cell-line and xenograft studies-suggests that ferroptosis induction by natural products and nano/exosome-enabled delivery platforms can suppress OS growth and sensitize tumors to standard chemotherapeutics in preclinical models, including selected drug-resistant settings. However, clinical translation will require rigorous PK/PD and biodistribution characterization, definition of a therapeutic index and off-tumor ferroptosis liabilities, validation in orthotopic/bone-microenvironment models, and biomarker-guided stratification to identify responsive OS subsets.
    Keywords:  Ferroptosis; apoptosis.; lipid peroxidation; nanotechnology; natural products; osteosarcoma
    DOI:  https://doi.org/10.2174/0109298673457795260526143914
  21. Regen Biomater. 2026 ;13 rbag109
    Plant-derived extracellular vesicles for drug delivery: current and future.
    Fengdan Xu, Yuling Liu, Qiling Zhang, Ruying Tang, Hui Li, Hongjun Yang, Longfei Lin.
      Plant-derived extracellular vesicles (PDEVs) have attracted considerable attention as natural drug delivery vehicles owing to their low immunogenicity, excellent biocompatibility, cross-kingdom delivery capability and intrinsic targeting properties. They naturally encapsulate a variety of bioactive components that can synergize with loaded drugs, while the vesicles exhibit good stability under simulated gastrointestinal conditions. This review focuses on the structure-property-function relationships of PDEVs in drug delivery. It systematically compares current drug loading strategies and evaluation approaches, particularly engineered loading technologies and composite delivery systems. Furthermore, it summarizes the applications of PDEV-based delivery systems in disease therapy, vaccine development, cosmetics and nutraceuticals. Finally, we propose an evaluation framework to facilitate clinical translation, providing theoretical support for advancing these systems toward practical use.
    Keywords:  challenges and solutions; development trends; drug delivery systems; loading methods; plant-derived extracellular vesicles
    DOI:  https://doi.org/10.1093/rb/rbag109
  22. Mater Today Bio. 2026 Aug;39 103370
    A flexibility-driven delivery strategy for cationic liposomes to enhance tumor penetration and promote membrane fusion-mediated cellular entry.
    Lifeng Luo, Xiaonan Liu, Yuqing Cai, Yiran Zhang, Yifan Zhao, Zhenqiang Song, Ziwen Meng, Tian Xie, Fenghua Meng, Wenxing Gu.
      Cationic liposomes have emerged as a promising delivery vehicle for chemotherapy. However, their strong electrostatic interaction with tumor vascular endothelium and stroma lead to predominant accumulation at the periphery, thereby restricting deep tumor penetration. Herein, we propose a mechanical programming strategy that modulates the flexibility of cationic liposomes to enhance their tissue permeability, delivery efficiency and antitumor efficacy. By incorporating sodium cholate as a flexibilizer, we engineered a cabazitaxel (CTX)-loaded cationic flexible liposome (CTX@CFL) with enhanced membrane fluidity and deformability. This flexibility-driven redesign shifted the cellular uptake mechanism from endocytosis to membrane fusion, facilitating direct cytosolic delivery and bypassing lysosomal degradation. Consequently, CTX@CFL demonstrated superior transendothelial transport, significantly deeper tumor penetration, and enhanced cytotoxicity compared to conventional cationic rigid liposomes. In vivo, CTX@CFL achieved markedly improved tumor accumulation, intratumoral distribution, and potent antitumor efficacy with favorable biocompatibility. This work establishes 'flexibility modulation' as a core design strategy that fundamentally overcomes the intrinsic delivery barriers of cationic liposomes. It provides a translatable engineering approach to unlock the full therapeutic potential of cationic liposomal systems in solid tumor therapy.
    Keywords:  Cationic liposome; Flexibility; Membrane fusion; Sodium cholate; Tumor permeation
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103370
  23. Hum Cell. 2026 Jul 02. pii: 97. [Epub ahead of print]39(7):
    Bone marrow mesenchymal stem cell-derived exosomes exert therapeutic effects on inflammatory bowel disease through miR-148a-3p/Ets-1-dependent inhibition of pyroptosis.
    Feilong Zhang, Ji Song, Yunjiao Zhang, Hejun Hu, Ping Zhou, Caixiao Xu, Meinan Zhan, Anna Hou, Xiangli Lin, Wenjuan Shen.
      Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory condition of the gastrointestinal tract, characterized by damage to intestinal epithelial cells (IECs) and inflammation. Mesenchymal stem cell-derived exosomes show therapeutic potential in IBD, but the underlying mechanisms remain unclear. This study investigates the therapeutic potential of bone marrow mesenchymal stem cell (BMSC)-derived exosomes and their molecular mechanism in IBD. We isolated and characterized exosomes from mouse BMSCs, confirming their typical size, morphology, and marker expression. In a dextran sulfate sodium (DSS)-induced mouse IBD model, administration of BMSC-derived exosomes alleviated disease severity, colon shortening, and histopathological damage. In LPS + ATP-stimulated IECs, BMSC-exos upregulated miR-148a-3p expression, enhanced cell viability, and suppressed pyroptosis-related proteins, including NOD-like receptor protein 3 (NLRP3), ASC, cleaved caspase-1, and the N-terminus of GSDMD (GSDMD-N), and inflammatory cytokines interleukin 1β (IL-1β), IL-18, tumor necrosis factor-α (TNF-α), and IL-6. Bioinformatics and dual-luciferase reporter assays identified E26 avian leukemia oncogene 1, 5' domain (Ets-1) as a direct target of miR-148a-3p. Ets-1 knockdown reversed the effects of miR-148a-3p inhibition on IEC pyroptosis and inflammation. In conclusion, BMSC-derived exosomes deliver miR-148a-3p to IECs, where it targets Ets-1 to suppress cellular pyroptosis and inflammatory responses, offering a novel therapeutic strategy for IBD.
    Keywords:  Exosomes; Inflammatory bowel disease; Mesenchymal stem cells; MiR-148a-3p; Pyroptosis
    DOI:  https://doi.org/10.1007/s13577-026-01403-2
  24. Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 102980
    Milk-derived extracellular vesicles loaded with miR-146a-5p as a novel therapeutic strategy for allergic airway inflammation.
    Chan-Gu Li, Qi Sun, Tian Tian, Zi-Cong Wu, Ying-Chun Xie, Xiao-Qing Liu, Zhi-Rou Zhou, Long-Xin Huang, Xiao-Hui Deng, Si-Lin Yu, Qing-Ling Fu.
      Previous studies have demonstrated that miR-146a-5p can effectively inhibit the function of group 2 innate lymphoid cells (ILC2s), which play a pivotal role in the initiation of allergic airway inflammation (AAI), thereby alleviating AAI. However, the application of miR-146a-5p faces challenges such as susceptibility to degradation and difficulty in crossing the cellular membrane. Extracellular vesicles (EVs), which naturally transport proteins and nucleic acids, have been proposed as promising RNA delivery vehicles. EVs can protect microRNAs (miRNAs) from degradation and facilitate their penetration across cellular membranes. However, the lack of scalable sources of EVs remains a challenge for their mass production, particularly in clinical application. Bovine milk has emerged as an advantageous source for the large-scale production of EVs because of its low cost and easy accessibility. Moreover, bovine milk-derived EVs (mEVs) have shown low immunogenicity and outstanding cross-species biosafety. In this study, we present the manufacturing methods and immune regulatory effects of mEVs loaded with miR-146a-5p (miR146a-5p-mEVs). Our findings indicated that mEVs exhibited outstanding biosafety and did not elicit significant systemic toxicity. Importantly, miR146a-5p-mEVs exhibited significant immunoregulatory functions in AAI, suggesting that miR146a-5p-mEVs could serve as a novel strategy for the treatment of allergic airway disease.
    Keywords:  MT: delivery strategies; airway allergic inflammation; group 2 innate lymphoid cells; miRNA delivery; milk-derived extracellular vesicles
    DOI:  https://doi.org/10.1016/j.omtn.2026.102980
  25. Microbiol Spectr. 2026 Jun 29. e0421925
    Arginine-substituted Mastoparan-C derivatives combat dual bacterial pathogens: in vitro mechanistic insights and in vivo efficacy in polymicrobial wounds.
    Luyao Zhang, Anqi Huang, Mingyu Lu, Jingjing Wang, Yingyu Wang, Fei Mo, Mingchun Liu.
      The synergistic interactions in multi-pathogen infections compromise wound healing and limit therapeutic efficacy. In this study, we designed and synthesized arginine-substituted derivatives of the antimicrobial peptide Mastoparan-C (MP-C). Among them, Arg²MP-C and Arg4.11.12MP-C exhibited potent, broad-spectrum activity against both Escherichia coli and Staphylococcus aureus. Their enhanced antibacterial activity is associated with increased positive charge and optimized hydrophobicity. Mechanistically, both peptides employ a dual-target strategy, disrupting bacterial membranes and binding genomic DNA; Arg²MP-C acted most rapidly against the E. coli envelope, while Arg4.11.12MP-C caused the strongest membrane damage to S. aureus. In a murine polymicrobial wound model, Arg²MP-C treatment nearly achieved complete wound closure by day 10, significantly reduced bacterial loads, and promoted tissue regeneration. This study demonstrates that arginine engineering can yield peptides with potent, multi-mechanistic action, identifying Arg²MP-C as a promising candidate for combating polymicrobial wound infections.
    IMPORTANCE: Wounds infected with multiple bacterial species are notoriously difficult to treat, often leading to poor healing and limited effectiveness of existing therapies. In this study, we developed new antimicrobial peptides by introducing arginine substitutions into a natural peptide called Mastoparan-C. Two of our engineered peptides, Arg²MP-C and Arg4.11.12MP-C, showed potent activity against two common wound pathogens, Escherichia coli and Staphylococcus aureus. These peptides work through a dual mechanism: disrupting bacterial membranes and binding to bacterial DNA. In a mouse model of mixed-infection wounds, treatment with Arg²MP-C led to nearly complete wound closure by day 10, drastically reduced bacterial counts, and promoted tissue repair. Our findings highlight arginine engineering as a promising strategy to create next‑generation antimicrobial agents that can effectively combat complex polymicrobial wound infections, addressing a critical unmet need in clinical wound care.
    Keywords:  antimicrobial peptides; arginine modification; membrane disruption; structure-activity relationship; wound polymicrobial infection
    DOI:  https://doi.org/10.1128/spectrum.04219-25
  26. Acta Pharm Sin B. 2026 Jun;16(6): 3506-3539
    Engineered cell-biomimetic nanosystems for anti-inflammatory therapy: Targeting, neutralization and immunomodulation.
    Ruiyao Liu, Wuting Dai, Wenbo Zhou, Weilin Li, Yuan Yu.
      Inflammation is a complex and dynamic immune response triggered by tissue injury or pathogen invasion, playing a critical role in restoring tissue homeostasis. However, excessive inflammation can lead to tissue damage and exacerbate the progression of various diseases. Issues such as off-target effects and insufficient dynamic regulation pose key challenges to precise modulation of complex inflammatory processes, thereby enhancing efficacy while minimizing adverse effects. Engineered cell-biomimetic nanosystems (ECNs), including membrane-coated nanoparticles, extracellular vesicles (ECVs), and cell-nanoparticle hybrids, are highly adaptable biomimetic platforms with tunable physicochemical properties. Beyond carrier functions, ECNs are capable of actively responding to inflammation-related targets and interacting with the immune microenvironment, thereby promoting the dynamic regulation of inflammation. This review summarizes recent advances in ECNs, with an emphasis on targeting mechanisms and key strategies for inflammatory intervention. These include precise targeting of inflamed tissues, biological neutralization of toxins and overexpressed inflammatory factors to interrupt the inflammatory cascade, and immunomodulatory functions that balance immune responses to achieve activation or suppression. Physical, chemical, and biological engineering strategies for modifying cells and cell membranes for inflammation targeting are also discussed. As an emerging platform for targeted drug delivery and immune regulation, ECNs provide innovative technological approaches for inflammation therapy.
    Keywords:  Biological neutralization; Cell-biomimetic nanosystem; Engineered cell/cell membrane; Immune modulation; Inflammation; Microenvironment; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.apsb.2026.04.002
  27. J Adv Res. 2026 Jul 03. pii: S2090-1232(26)00522-9. [Epub ahead of print]
    Bioengineered JMJD3-PROTAC targeted epigenetic immunotherapy strategy for diabetic periodontitis.
    Yuzhao Cheng, Yan Dong, Wei Qiao, Guodong Yang, Liang Kong, Mengying Wei, Zhongshan Wang.
       OBJECTIVES: This study aimed to develop and evaluate a targeted nanotherapeutic system to degrade the nonenzymatic form of JMJD3 and thereby restore immune balance and tissue repair in diabetic periodontitis.
    METHODS: A pH/reactive oxygen species (ROS)-responsive nanoplatform (P-PLGA@MM) was engineered using diselenium-bonded poly(lactic-co-glycolic acid) (PLGA) loaded with a JMJD3-targeting proteolysis-targeting chimera (PROTAC) and camouflaged with macrophage membranes. In vitro and in vivo models of diabetic periodontitis were used to assess cellular uptake, JMJD3 degradation, anti-inflammatory efficacy, and tissue regeneration.
    RESULTS: P-PLGA@MM exhibited macrophage-specific uptake and lysosomal escape, enabling efficient intracellular release of PROTAC. This facilitated the selective degradation of JMJD3's nonenzymatic activity through the ubiquitin proteasome pathway. In vitro, the nanoplatform suppressed macrophage M1 polarization and reduced inflammatory cytokines. In vivo, local injection of P-PLGA@MM in diabetic mice promoted collagen regeneration, reduced alveolar bone loss, and improved healing without systemic toxicity.
    CONCLUSIONS: This study demonstrates that targeted nano-delivery of PROTAC for JMJD3 degradation effectively alleviates inflammation and promotes periodontal regeneration in diabetic periodontitis. The P-PLGA@MM system presents a promising strategy for localized epigenetic therapy in chronic inflammatory diseases.
    Keywords:  DiabeticPeriodontitis; MacrophageEpigenetic; Nanoparticle; PROTAC
    DOI:  https://doi.org/10.1016/j.jare.2026.07.004
  28. Oral Health Prev Dent. 2026 Jun 30. 24 489-497
    Treatment of Severe Periodontitis using Exosome-Mediated Combination Therapies: A Retrospective Cohort Study.
    Scott Froum, Nathan E Estrin, Hyun Jae Cho, Nima Farshidfar, Paras Ahmad, Richard J Miron.
       PURPOSE: This pilot retrospective case series aimed to evaluate the 6-month clinical outcomes and safety of a combined regenerative protocol utilizing exosomes specifically designed for periodontal regeneration (Periosomes), with 90% anorganic bovine bone/10% collagen (ABBMC), and horizontal platelet-rich fibrin (H-PRF) for the treatment of advanced periodontal osseous defects.
    MATERIALS AND METHODS: This study analyzed stage-III (severe) periodontitis patients (from poor to hopeless prognosis) who underwent periodontal surgery using Periosomes with an ABBC/H-PRF scaffold with a 6-month follow-up. Complete periodontal charting, including probing depth (PD), gingival margin (GM), bleeding on probing (BOP), clinical attachment loss (CAL), gingival index (GI), plaque index (PI), and tooth mobility, was assessed at baseline and the follow-up. The study included 13 patients (8 females and 5 males) aged 29 to 73 years, with 23 periodontal defects of one-walled (60.9%) and two-walled (39.1%) defect morphology.
    RESULTS: The sites treated with Periosomes showed statistically significant reductions in PD from baseline to six months in one-walled defects (8.50 ± 2.41 mm to 3.14 ± 0.77; p 0.0001) and two-walled defects (7.56 ± 1.13 mm to 3.22 ± 0.44; p 0.0001) as well as in CAL from 9.14 ± 3.01 mm to 4.79 ± 2.17 (p 0.0001) in one-walled defects and from 7.22 ± 1.56 mm to 3.56 ± 1.01 (p 0.0001) in and two-walled defects. Furthermore, frequency distribution analysis found that 96% of sites attained residual PD 5 mm and 92% showed CAL gains ≥3 mm at the 6-month follow-up.
    CONCLUSION: The combined use of Periosomes, ABBMC, and H-PRF was associated with favorable short-term clinical improvements in advanced periodontal osseous defects with no reported adverse events. To our knowledge, this is the first human clinical study assessing the use of exosomes in periodontal regenerative therapy. However, controlled clinical trials with comparator groups and longer follow-up are necessary to evaluate the independent contribution of exosomes in periodontal regeneration.
    Keywords:  bone regeneration; exosomes; extracellular vesicles; periodontitis; tissue scaffolds
    DOI:  https://doi.org/10.3290/j.ohpd.c_2745
  29. Acta Pharm Sin B. 2026 Jun;16(6): 3540-3581
    Engineered extracellular vesicles for combinatorial cancer therapy and imaging.
    Anita S La'ah, Nashmin Fayazi Hosseini, Choongmo Kang, Amirhossein Ahmadieh-Yazdi, Mohsen Sheykhhasan, Piao Yang, Armita Ghotaslou, Hamed Manoochehri, Yun Suk Huh, Heemin Kang, Pooyan Makvandi.
      Cancer treatment has advanced significantly over the past few decades, resulting in improved patient survival outcomes. However, challenges like drug resistance, off-target effects, and systemic toxicity continue to persist. These underscore the importance of modified extracellular vesicles (EVs) as a versatile and innovative platform for delivering combination therapies for cancer. This review highlights the utilization of biocompatible engineered EVs to inhibit cancer progression with reduced side effects. Further, outlining the promising approach to cancer treatment through combination therapies and imaging-guided strategies. Additionally, this review explored the biogenesis and various sources of EVs, which provides clear insights into future directions.
    Keywords:  Cancer diagnosis; Cancer therapy; Combination therapy; Drug delivery; Gene therapy; Imaging-guided therapy; Immunotherapy; Modified extracellular vesicles
    DOI:  https://doi.org/10.1016/j.apsb.2026.03.054
  30. J Mater Chem B. 2026 Jul 01.
    Bioinspired electrospun nanofibrous dressings loaded with Mentha-derived exosome-like vesicles for antibacterial and immunomodulatory burn healing.
    Yuansong Liu, Yingying Zhu, Xinyu Gao, Yuhan Miao, Qianying Xie, Ying Li, Enzhe Liu, Jun Ren, Xiansong Wang.
      Deep partial-thickness burns present a significant therapeutic challenge due to susceptibility to multidrug-resistant bacterial infections and persistent inflammation. Conventional grafts and dressings often fail to address the complex "inflammatory storm" microenvironment. Herein, inspired by the traditional medicinal use of Mentha for heat dissipation and dermatitis relief, we engineered a bioactive nanofibrous dressing via electrostatic self-assembly of poly(γ-glutamic acid) (γ-PGA) and ε-poly-L-lysine (ε-PLL), loaded with Mentha-derived exosome-like vesicles (mEVs). This biomimetic mEVs@γ-PGA@ε-PLL (mEVs@PP) scaffold mimics the extracellular matrix (ECM), providing physical protection and high porosity. Mechanistically, the sustained release of mEVs reprograms the immune microenvironment by downregulating pro-inflammatory cytokines (IL-1β, IL-6), while simultaneously exhibiting potent broad-spectrum antibacterial activity against S. aureus, E. coli, and P. aeruginosa. Furthermore, the dressing significantly promotes angiogenesis and accelerates re-epithelialization via the potential involvement of the HIF-1α/VEGF pathway. In vivo assessments confirm that mEVs@PP enhances burn wound healing with superior tissue remodeling compared to commercial treatments. This study presents a novel "antibacterial-immunomodulatory" strategy, offering a promising, cost-effective solution for severe burn management.
    DOI:  https://doi.org/10.1039/d6tb00281a
  31. BMC Med. 2026 Jun 29.
    Engineered iMSCs delivering wild-type IL-2 achieve dose-sparing tumor control via CD25-dependent CD8+ T-cell activation.
    Shuqing Tang, Mengting Han, Peiyun Wang, Fan Lu, Ying Zhang, Zhixing Li, Shenglan Zhou, Yusang Zhang, Zujia Wang, Junya Zhao, Yuquan Luo, Zhixin Tian, Mai Feng, Guanshan Zhu, Lingqian Wu, Desheng Liang.
       BACKGROUND: Interleukin-2 (IL-2), the first FDA-approved cytokine-based immunotherapy, can induce durable antitumor responses but its broader use is curtailed by life-threatening, dose-dependent toxicities. This narrow therapeutic window has limited clinical translation for decades. Genetically engineered mesenchymal stromal cells (MSCs) have emerged as attractive IL-2 delivery vehicles due to their low immunogenicity and intrinsic tumor-homing capacity.
    METHODS: Human induced pluripotent stem cells (iPSCs) were edited by CRISPR/Cas9 to knock in wild-type IL-2 (wtIL-2) or a receptor-biased variant (IL-2v) into the B2M or B3 safe-harbor loci, generating cytokine-secreting iPSC-derived MSCs (iMSCs). Antitumor activity was evaluated in co-cultures of iMSCs, tumor cells, and peripheral blood mononuclear cells (PBMCs) by flow cytometry. In vivo, systemically administered iMSCs were tracked by live imaging in mice bearing subcutaneous tumors to assess biodistribution and tumor targeting. Tumor control was monitored by longitudinal tumor growth and end-point volume; toxicity was evaluated by lung wet weight and blood biochemistry. Immune cell states within the tumor microenvironment were characterized by flow cytometry and RNA sequencing. Data (mean ± s.e.m.) were analyzed in GraphPad Prism using t-tests, ANOVA, or Kruskal-Wallis tests, as appropriate (n = biological replicates; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).
    RESULTS: Surprisingly, we found that under low-dose conditions, only iMSCs with IL-2 overexpression-but not unmodified iMSCs or free IL-2 alone-induced robust upregulation of CD25 on CD8+ T cells. This effect likely increases T-cell sensitivity to wtIL-2 and may contribute to the improved tumor control achieved at reduced IL-2 doses. Systemic administration of wtIL-2-iMSCs preferentially activated intratumoral T cells and achieved tumor growth inhibition comparable to high-dose rhIL-2 in our model, while attenuating systemic toxicity. Transcriptomic analysis indicated that wtIL-2-iMSCs enhanced effector programs in tumor-infiltrating CD8⁺ T cells more effectively than rhIL-2 under the tested conditions. Notably, targeted integration of wtIL-2 at a novel locus within the B2M region (B3-wtIL-2-iMSCs) led to a higher transgene expression and further augmented antitumor activity in vitro and in vivo with no clear increase of systemic toxicity. Moreover, B3-wtIL-2-iMSCs exhibited synergistic antitumor effects when combined with anti-PD-1 blockade, thereby strengthening overall tumor control.
    CONCLUSIONS: These findings point to a mechanism by which iMSC-delivered IL-2 reshapes the tumor microenvironment through CD25-dependent CD8⁺ T-cell activation. Furthermore, the results support the concept that this platform enables a more dose-efficient cytokine delivery strategy with an improved safety profile, thereby facilitating the clinical translation of off-the-shelf allogeneic iMSC-based gene therapies.
    Keywords:  CD25 signaling; Engineered iMSCs; Targeted delivery; Tumor immunotherapy; Wild-type IL-2
    DOI:  https://doi.org/10.1186/s12916-026-05035-z
  32. Curr Drug Targets. 2026 Jun 30.
    Extracellular Vesicles from Mesenchymal Stem Cells Alleviate Spinal Cord Injury via the miR-486-5p/PTEN/PI3K/AKT Pathway.
    Yuhong Chen, Jinghui Zhu, Xiujuan Wang, Faxiang Xu, Yuan Zhou, Xian Zhang, Jianhuang Wu, Yongsheng Xu.
       INTRODUCTION: Spinal Cord Injury (SCI) is a severe central nervous system disorder with limited effective treatments. Mesenchymal stem cell (MSC)-derived exosomes have emerged as important mediators of intercellular communication and carry microRNAs with potential neuroprotective properties. This study aimed to explore the role and underlying mechanism of human umbilical cord MSC (hUMSC)-derived exosomal miR-486-5p in experimental SCI.
    METHODS: Exosomes were isolated from hUMSCs and characterized by transmission electron microscopy, nanoparticle tracking analysis, and exosomal marker expression. A rat SCI model and an LPS-induced PC12 cell inflammatory injury model were established. Histological injury and apoptosis were assessed by HE staining and TUNEL assay. Inflammatory cytokine levels were measured by ELISA. Cell viability, apoptosis, and gene and protein expression were evaluated using CCK-8 assay, flow cytometry, qPCR, and western blotting. A dual-luciferase reporter assay was performed to validate the interaction between miR-486-5p and PTEN.
    RESULTS: hUMSC-derived exosomes attenuated spinal cord tissue damage, reduced neuronal apoptosis, and suppressed inflammatory cytokine production in vivo and in vitro. Inhibition of exosomal miR-486-5p partially reversed these protective effects. Mechanistically, miR-486-5p directly targeted the 3'-UTR of PTEN, leading to reduced PTEN expression and enhanced phosphorylation of AKT and mTOR.
    DISCUSSION: These findings indicate that exosomal miR-486-5p contributes to the regulation of apoptosis- and inflammation-associated molecular events following SCI, primarily through modulation of the PTEN/AKT/mTOR signaling pathway. Given the experimental design, these results should be interpreted as mechanistic insights rather than evidence of functional recovery.
    CONCLUSION: hUMSC-derived exosomal miR-486-5p alleviates apoptosis and inflammation following SCI by targeting PTEN and activating the AKT/mTOR pathway. These findings provide mechanistic support for the potential application of exosome-based miRNA therapy in SCI.
    Keywords:  PTEN; Spinal cord injury; exosomes; mesenchymal stem cell; miR-486-5p; qPCR
    DOI:  https://doi.org/10.2174/0113894501433511260311202908
  33. J Extracell Biol. 2026 Jul;5(7): e70160
    Bovine Milk-Derived Extracellular Vesicles as Emerging Drug Delivery Platforms: Current Advances, Applications and Challenges.
    Martina Brattini, Michelle D'Urso, Sofia Mariotto, Elena Butturini.
      Extracellular vesicles (EVs) are nanosized lipid bilayer particles naturally secreted by cells, mediating intercellular communication and transporting diverse bioactive molecules. Among alternative EV sources, bovine milk-derived EVs (BMEVs) have emerged as promising platforms for drug delivery due to their accessibility, scalability, stability and promising biocompatibility, although their long-term safety profile, particularly for engineered or cargo-loaded formulations, still requires further investigation. BMEVs can encapsulate small molecules, natural polyphenols and nucleic acids, enhancing bioavailability, protecting cargo from degradation and facilitating functional delivery. Recent studies demonstrate their potential for oral administration and their intrinsic therapeutic properties, including antioxidant, anti-inflammatory, and immunomodulatory activities. Moreover, the increasing number of patents highlights their translational and commercial relevance in therapeutic, cosmetic and nutraceutical applications. Despite these promising features, challenges remain in standardizing isolation protocols, optimizing cargo loading, ensuring batch reproducibility and evaluating long-term safety. Addressing these gaps is essential to enable clinical translation and establish BMEVs as versatile drug delivery platforms. Trial Registration: ClinicalTrials.gov identifier: NCT07402083.
    Keywords:  drug delivery; extracellular vesicles; milk
    DOI:  https://doi.org/10.1002/jex2.70160
  34. Small. 2026 Jul 03. e12872
    Collagenase-Coated Polymeric Drug/siRNA Nanoparticles Overcome ECM and Regulate Metabolic Reprogramming of Fibroblasts for Alleviating Pulmonary Fibrosis.
    Shihong Cheng, Pingping Luo, Huirong Chi, Yiqiu Zhang, Chujie Li, Xiyan Wang, Yang Liu, Guolin Li.
      Pulmonary fibrosis (PF) is a progressive lung disease characterized by abnormal extracellular matrix (ECM) accumulation, leading to respiratory dysfunction and eventual respiratory failure. The pathogenesis involves fibroblast migration, proliferation, and activation via the CXCL12/CXCR4 axis, resulting in collagen deposition and ECM accumulation. Additionally, this axis drives epithelial-mesenchymal transition (EMT) and angiogenesis. Under hypoxic conditions induced by ECM accumulation, pyruvate dehydrogenase kinase 1 (PDK1) further promotes fibroblasts differentiation into myofibroblasts by enhancing metabolic reprogramming towards glycolysis. To target these multifaceted pathological processes, a collagenase-coated polymeric drug/siRNA delivery system is engineered. This system comprises PPLFazo, hypoxia-responsive polymer of plerixafor (CXCR4 inhibitor), loaded with PDK1 siRNA (siPDK1) and encapsulated by collagenase-conjugated polyglutamic acid. Upon inhalation, the collagenase degrades ECM barrier, facilitating PPLFazo/siPDK1 recognition and endocytosis by fibroblasts. In the hypoxic microenvironment, both plerixafor monomers and siPDK1 are released, exerting their targeted therapeutic effects. Pharmacodynamic evaluations in murine PF models demonstrated that PPLFazo/siPDK1@G-CLG reduced myofibroblast accumulation, decreased collagen deposition, and attenuated abnormal fibrotic tissue growth in the lungs. These findings collectively indicate substantial amelioration of PF. By simultaneously targeting multiple pathological pathways, this system offers a novel strategy to combat this challenging disease, potentially improving patient outcomes.
    Keywords:  CXCR4/CXCL12; metabolic reprogramming; polymeric drug; pulmonary fibrosis; siRNA delivery
    DOI:  https://doi.org/10.1002/smll.202512872
  35. Theranostics. 2026 ;16(13): 7466-7494
    Engineering spherical nucleic acids for precision cancer therapy: design strategies and medical applications.
    Yilin Wang, Wenbing Wu, Fuli Yao.
      Malignant tumor treatment still faces issues like insufficient targeting, drug resistance, and immunosuppression. Spherical nucleic acids (SNAs), with their three-dimensional core-shell structure and densely packed, radially oriented oligonucleotide shell, enable transfection-free cellular uptake and provide nuclease resistance and stability. This review examines SNA engineering strategies and their impact on precision oncology. Functionalization with antibodies, aptamers, or antisense oligonucleotides enables SNAs to target key molecules such as human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and toll-like receptors (TLRs). Advances in stimuli-responsive, self-assembled, liposomal, and peptide-based carrier systems facilitate controlled drug release and modulation of the tumor microenvironment (TME). Diagnostic applications of SNAs include electrochemical, fluorescent, and colorimetric sensing systems for detecting biomarkers such as exosomes, miRNAs, alpha-methylacyl-CoA racemase (AMACR), and telomerase. Therapeutically, SNAs co-deliver chemotherapeutics and immunoadjuvants, support cancer vaccines, and exert efficacy in various tumors, including the central nervous, reproductive, digestive, hematological, barrier, and respiratory systems. Early clinical studies indicate a favorable biosafety profile, but issues remain regarding delivery efficiency, target selectivity, scalability, and long-term safety. Progress toward biodegradable, machine-learning-guided SNA platforms may soon make this nanotechnology a fundamental part of personalized, precision cancer medicine.
    Keywords:  biomaterial; cancer therapy; immunotherapy; spherical nucleic acid; targeted delivery
    DOI:  https://doi.org/10.7150/thno.132738
  36. ACS Synth Biol. 2026 Jul 01.
    Engineering Modular Cargo Loading Strategies for Carboxysome-Derived Protein Particles.
    Claudia A Mak, Rachelle M Baumann, Anthony G Vecchiarelli.
      Bacterial microcompartments (BMCs) are a diverse and widespread class of self-assembling protein-based organelles consisting of a semipermeable protein shell encapsulating an enzymatic core. Isolated BMC shell proteins have been shown to assemble into alternative superstructures such as flat sheets and nanotubes. The self-assembly and modularity of BMC shell proteins make them of great interest as modular platforms for applications involving scaffolding, immobilization, and compartmentalization. While the assembly of BMC shell proteins into higher-order structures has been well-studied, the design of controllable and modular cargo loading is underdeveloped in comparison. Recently, we reported the pH-controlled assembly of CcmK2, the major hexameric shell protein of the β-carboxysome BMC, into monodisperse mesh-like microscale particles. Here, we develop a suite of encapsulation strategies for stochastic or targeted loading of various cargos, as well as the direct conjugation of cargo to CcmK2 particles. Our systematic analysis demonstrates that cargo loading and particle assembly can be modulated by the choice of recruitment strategy and the order of cargo introduction. Our findings also reveal a cooperative cargo loading mechanism during assembly that influences particle sizing and apparent morphology. Our study serves as a blueprint for the rational design of tunable cargo loading into engineered BMC-derived microcompartment systems for diverse biotechnological applications.
    Keywords:  bacterial microcompartment; biomaterial; carboxysome; cargo loading; protein particle; self-assembly
    DOI:  https://doi.org/10.1021/acssynbio.6c00354
  37. Biomater Res. 2026 ;30 0359
    Biomimetic Nanogels Programmed for Irreversible-Electroporation-Primed Tumor Microenvironments to Elicit Durable Antitumor Immunity.
    Jun-Hyeok Han, Ha Eun Shin, Chun Gwon Park, Hyun-Do Jung, Jung-Hoon Park, Ji Hoon Jeong, Yong Taik Lim, Dong-Hyun Kim, Wooram Park.
      Irreversible electroporation (IRE) remodels the tumor microenvironment to enhance biomaterial and nanoparticle (NP) delivery and immune activation, making combinational IRE-nanomedicine a promising approach for effective cancer treatment. Here, we present a rational combination strategy that integrates IRE-induced immune modulation with M1 macrophage-membrane (M1-m)-coated nanogels to amplify and prolong antitumor immune responses. Transcriptomic and immunological profiling after IRE revealed a transient up-regulation of immune and inflammatory pathways, particularly the recruitment of macrophages and dendritic cells, followed by a rapid decline over time. To exploit this transient inflammatory state, we engineered an M1-m-coated nanogel hydrogel co-loaded with graphene quantum dots as a fluorescence probe and the immune modulator zoledronic acid (M1-GAZ). The IRE-enhanced tumor-targeting efficiency of M1-m-coated NPs was confirmed by comparing the tumor-targeting efficiency with other NP formulations including gold NPs (negatively or positively charged), lipid-based NPs (liposomes and lipid NPs, negatively or positively charged), and macrophage (M0 or M1) cell-membrane-coated NPs. Subsequently, the combination of IRE with intravenously injected M1-GAZ markedly increased the infiltration of activated macrophages and dendritic cells, resulting in superior tumor suppression and prolonged survival compared to monotherapies. This study demonstrates that engineering biomimetic M1-m-coated nanogels to synergize with IRE-induced tumor microenvironment remodeling enables selective delivery and durable immune activation, providing a robust platform for synergistic IRE cancer immunotherapy.
    DOI:  https://doi.org/10.34133/bmr.0359
  38. Asian J Pharm Sci. 2026 Jun;21(3): 101172
    An opposite pH-responsiveness "gating" strategy: Intelligent sporopollenin exine armor for targeted therapy of colitis.
    Jun Liu, Zifang Ding, Jianxiong Wei, Yuanqing Li, Xiaoqing Wang, Xiaodan Yan, Dan Li, Tiantian Ye, Shujun Wang, Jin Sun.
      Conventional therapy for ulcerative colitis (UC) is often limited by insufficient colonic targeting, short local retention and poor cellular drug uptake at lesion sites. Here, we develop a biomimetic colon-targeted delivery system based on an opposite pH-responsive "gating" strategy. Chrysanthemum sporopollenin (spo) microcapsules with a characteristic spiny architecture serve as the core carrier. Spo exhibits acid-induced contraction and alkali-induced expansion, with germinal apertures opening progressively as pH increases. In contrast, chitosan-butyrate complex (CBC) swells into a gel under acidic conditions but contracts and precipitates in alkaline environments. After drug loading into the spo, surface coating with CBC seals the germinal apertures, constructing an intelligent gate. In gastric fluid, the CBC layer gels and blocks apertures to prevent premature drug release. In intestinal fluid, CBC contracts and precipitates to open the gate; meanwhile, spo expands to further widen germinal apertures and facilitate drug release. The spiny morphology of spo, combined with the mucoadhesive properties of chitosan and active targeting of butyrate, collectively enhances intestinal adhesion and retention, enabling precise colonic drug release and accumulation. Mesalazine is formulated into liposomes to improve aqueous solubility and stability, which enhances cellular uptake and bioavailability, thereby exerting synergistic anti-inflammatory effects with butyric acid at inflamed sites. The chrysanthemum sporopollenin-based gated microcapsules exhibit favorable pH-responsive release, enhanced mucoadhesion and potent synergistic anti-inflammatory activity. This work provides a promising multifunctional targeted delivery strategy for UC therapy and establishes a novel, versatile design concept termed the opposite pH-responsive dual-gating mechanism, which supports the development of oral colon-targeted carriers capable of navigating complex gastrointestinal environments.
    Keywords:  5-aminosalicylic acid; Butyric acid; Chrysanthemum sporopollenin; Colon-targeted; Drug delivery system; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.ajps.2026.101172
  39. Theranostics. 2026 ;16(13): 7442-7465
    Self-synergizing mutual prodrug liposomes for targeted cancer therapy via redox-amplified Pin1 inhibition.
    Nuri Kim, Ilseob Kim, Hanui Jo, Nanhee Song, Sangmin Jo, Suyeon Lee, Hoechang Kim, Changjin Lim, Dongwon Lee.
       Rationale: Combination chemotherapy often suffers from poor pharmacokinetics, asynchronous drug delivery, and limited synergism. We anticipated that combining all-trans retinoic acid (atRA) with a quinone methide (QM) precursor would promote intracellular reactive oxygen species (ROS) accumulation through distinct yet complementary mechanisms. We further hypothesized that this redox disruption could ultimately suppress the oncogenic protein Pin1, resulting in synergistic anticancer effects.
    Method: We designed proxiRQ, a mutual prodrug in which atRA and a QM precursor are linked via an esterase-cleavable bond. Owing to the amphiphilic nature of proxiRQ, it was able to self-assemble with dipalmitoyl phosphatidylcholine (DPPC) to form cholesterol-free liposomes. We obtained tL-proxiRQ by further surface modification with poly(γ-glutamic acid) (γPGA), which improved systemic circulation and enhanced tumor accumulation. Subsequently, we evaluated physicochemical properties, esterase-triggered drug release, cellular redox modulation, and in vitro and in vivo antitumor efficacies.
    Results: tL-proxiRQ, featuring a high drug loading capacity (37 mol%) and colloidal stability, synchronously released atRA and QM upon esterase activation in tumor cells. QM-mediated glutathione (GSH) depletion amplified atRA-induced oxidative stress, thereby enhancing Pin1 expression inhibition. Compared to the free drug combination, tL-proxiRQ demonstrated significantly enhanced cytotoxicity, greater downregulation of Pin1, and enhanced apoptosis induction. In vivo, tL-proxiRQ achieved potent tumor growth inhibition in the MCF-7 xenograft model with minimal systemic toxicity.
    Conclusion: This study validates proxiRQ as a self-synergizing mutual prodrug and introduces tL-proxiRQ as a rationally engineered nanoplatform that integrates mutual prodrug chemistry, synergistic redox modulation, and targeted liposomal delivery to overcome the key limitations of conventional combination therapy.
    Keywords:  Pin1; all-trans retinoic acid; cancer; liposome; prodrug; redox homeostasis
    DOI:  https://doi.org/10.7150/thno.131597
  40. Curr Urol. 2026 Jul;20(4): 219-234
    Advancements in delivery systems for in vivo chimeric antigen receptor T-cell therapy in urological diseases.
    Yuxiao Li, Wen Zhang, Dongqi Tang.
      Chimeric antigen receptor (CAR) T-cell therapy is a new type of highly precise and targeted immunotherapy for urological diseases. It has demonstrated significant therapeutic potential in chronic and autoimmune kidney diseases such as renal fibrosis and membranous nephropathy. However, owing to its high cost, low efficiency, and serious side effects, such as cytokine storm syndrome, a new generation of drugs has emerged to solve these problems. In vivo CAR T-cell therapy is a treatment method that directly modifies specific cells within the patient's body through various delivery systems. Nonviral vectors (nanoparticles and exosomes) and viral vectors (adeno-associated viruses and lentiviruses) can be engineered to achieve better therapeutic effects. By taking advantage of different delivery systems and minimizing their drawbacks, in vivo CAR T-cell therapy can improve the stability and targeting ability, reduce immunogenicity, and minimize side effects. This review summarizes the mechanisms of action and clinical applications of various delivery systems used in in vivo CAR T-cell therapy, highlighting their potential in the treatment of urological diseases. Through a deeper understanding of the construction and optimization of well-designed platforms, the development of optimal delivery systems has valuable implications for the establishment of new pharmaceuticals for in vivo CAR T-cell therapy in urological diseases.
    Keywords:  Delivery systems; Gene therapy; Immunotherapy; In vivo chimeric antigen receptor t-cell therapy; Urological diseases
    DOI:  https://doi.org/10.1097/CU9.0000000000000349
  41. J Food Sci. 2026 Jul;91(7): e71192
    Donkey Milk Exosomes Protect Against Dextran Sulfate Sodium-Induced Colitis by Delivering Anti-Inflammatory miRNAs and Reshaping Gut Microbiota.
    Qizhen Zhong, Gengli Huang, Guangyuan Liu, Zhuoru Ren, Zhouping Wang.
      Ulcerative colitis treatment is hindered by side effects, relapse, individual variability, and poor intestinal barrier repair. Milk‑derived exosomes (exo) are safe; carry anti‑inflammatory miRNAs/proteins; and regulate immunity, epithelial repair, and gut microbiota. Here, we isolated donkey milk exo and characterized them. Exo showed typical features (TSG101, CD63, CD9) and contained 1212 miRNAs, with eca‑let‑7 g and eca‑miR‑148a being most abundant. Oral exo administration in DSS‑induced colitis mice significantly reduced body weight loss, colon shortening, and disease activity index. Exo enhanced intestinal barrier by upregulating Occludin, Claudin‑1, and ZO‑1; lowered pro‑inflammatory cytokines (IL‑1β, IL‑6, TNF‑α); increased anti‑inflammatory IL‑10; and attenuated oxidative stress and neutrophil infiltration. Mechanistically, eca‑let‑7 g directly targeted TLR4 3'UTR to inhibit NF‑κB, while eca‑miR‑148a targeted NLRP3 3'UTR to suppress the NLRP3‑Caspase‑1‑IL‑18 axis. Moreover, exo reshaped gut microbiota by reducing pathogenic Bacteroides and Desulfovibrio and enriching beneficial Akkermansia muciniphila and Turicibacter. Collectively, donkey milk exo alleviate DSS‑evoked colitis through two distinct mechanisms: miRNA‑mediated suppression of inflammatory pathways and gut microbiota modulation. These findings support donkey milk exo as a natural, orally deliverable therapeutic option for inflammatory bowel disease.
    Keywords:  donkey milk exosomes; gut microbiota; miRNA; ulcerative colitis
    DOI:  https://doi.org/10.1111/1750-3841.71192
  42. Biomaterials. 2026 Jun 29. pii: S0142-9612(26)00439-4. [Epub ahead of print]335 124415
    Peptide coacervate-mediated siRNA delivery for dual PD-1/PD-L1 blockade to enhance colorectal cancer immunotherapy.
    Zilin Chen, Vaibavi Ramanujam, Syed Maricar, Yiting Liu, Congxi Huang, Liqi Wong, Anastasia Shebanova, Zhiming Ma, Yue Sun, Bertrand Czarny, Ali Miserez.
      Immune checkpoint blockade targeting the PD-1/PD-L1 axis shows limited efficacy in microsatellite-stable (MSS) colorectal cancer (CRC), primarily due to an immunosuppressive tumor microenvironment (TME) and insufficient T-cell activation. Here, we report a peptide coacervate-mediated siRNA delivery platform that enables coordinated gene silencing of PD-1 in T-cells and PD-L1 in tumor cells to enhance CRC immunotherapy. HBpep-SP coacervates (HCs) were functionalized with anti-CD3 antibodies to generate targeted coacervates (THCs), enabling efficient T-cell-targeted delivery of PD-1 siRNA, robust PD-1 knockdown, and enhanced T-cell effector function, as indicated by increased IL-2 and IFN-γ production. In parallel, HCs efficiently delivered PD-L1 siRNA into CRC cells, achieving significant PD-L1 knockdown. Dual checkpoint silencing in a co-culture system of T-cells and CRC cells synergistically enhanced T-cell proliferation and activation, leading to increased tumor cell apoptosis. Importantly, in a murine MSS CRC model, intratumoral co-administration of siPD-1@THC and siPD-L1@HC simultaneously suppressed PD-1 and PD-L1 expression within the TME, increased intratumoral T-cell abundance, and elevated pro-inflammatory cytokine levels, resulting in restored antitumor immunity and significant tumor growth inhibition. Collectively, this peptide coacervate-based dual-checkpoint RNA interference strategy provides a promising approach for advancing T-cell-mediated immunotherapy in MSS colorectal cancer.
    Keywords:  Colorectal cancer; Dual immune checkpoint silencing; PD-1/PD-L1 axis; Peptide coacervate; T-cell activation; T-cell targeting; siRNA delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124415
  43. Life Sci. 2026 Jun 27. pii: S0024-3205(26)00365-6. [Epub ahead of print]402 124556
    Soluble PD-1 drives renal fibrosis in CKD by disrupting immune homeostasis: Therapeutic mitigation via a targeted sPD-1 sequestration strategy.
    Yuting Zhang, Hongbin Peng, Xue Mi, Jipeng Li, Yang Zha, Mengting Wu, Xiaomeng Xu, Fang Zhao, Haichao Cao, Ye Chen, Rui Lu, Ya Zhao, Guodong Yang, Lijie He.
       AIMS: Renal interstitial fibrosis (RIF) drives chronic kidney disease (CKD) progression, with elevated soluble PD-1 (sPD-1) exacerbating chronic inflammation. This study aims to elucidate the pathogenic role of sPD-1 in RIF and evaluate "Exo-PD1"-a novel engineered extracellular vesicle strategy designed to sequester circulating sPD-1-as a targeted therapeutic intervention to mitigate renal fibrosis.
    MATERIALS AND METHODS: We analyzed serum and renal biopsy samples from clinical CKD cohorts and three distinct mouse models-unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI), and aristolochic acid I (AAI)-induced nephropathy-using ELISA, immunohistochemistry, and flow cytometry. Exo-PD1 was engineered by surface-functionalizing extracellular vesicles with avidin to load anti-PD-1 antibodies. The therapeutic efficacy and safety profiles of Exo-PD1 were systematically evaluated in vitro and in vivo.
    KEY FINDINGS: Elevated sPD-1 strongly correlated with RIF severity and T-cell hyperactivation in both patients and murine models, while exogenous sPD-1 exacerbated fibrosis. Exo-PD1 effectively sequestered circulating sPD-1, outperforming conventional antibodies through local adsorption. Furthermore, Exo-PD1 treatment significantly attenuated T-cell hyperactivation, blunted inflammatory responses, and reduced key fibrotic markers (α-SMA, collagen I) across models with minimal systemic toxicity.
    SIGNIFICANCE: sPD-1 acts as a critical mediator of renal fibrosis by disrupting immune homeostasis. The biocompatible Exo-PD1 platform effectively intercepts circulating sPD-1, disrupting the inflammation-fibrosis crosstalk and offering a highly translational therapeutic approach to halt CKD progression.
    Keywords:  Exosome; PD-1/PD-L1; Renal fibrosis; T-cell activation; sPD-1
    DOI:  https://doi.org/10.1016/j.lfs.2026.124556
  44. Facial Plast Surg Clin North Am. 2026 Aug;pii: S1064-7406(26)00039-8. [Epub ahead of print]34(3): 395-409
    The Role of Human Placental Mesenchymal Stem Cell Derived Exosomes in Wound Healing and Scar Therapy.
    Greg Chernoff, Jenna Himelstein.
      Exosomes are a subtype of extracellular vesicles, critical for intercellular communication. They are released from a cell via exocytosis, after which they travel through the extracellular fluid until they reach a target cell. Research in the fields of cellular medicine, regenerative and stem cell therapy continues to grow exponentially. Deciphering the biological properties of mesenchymal stem cells-exosomes as cell-free therapeutic tools is important for wound healing and cutaneous regeneration. The future is also bright for genetically engineering exosomes for targeted diagnostic and therapeutic applications.
    Keywords:  Exosomes; Extracellular vesicles; Scar therapy; Wound healing
    DOI:  https://doi.org/10.1016/j.fsc.2026.05.004
  45. Bioconjug Chem. 2026 Jul 01.
    SpyCatcher-Engineered Ferritin Nanocages Enable Dual-Receptor Targeting for Enhanced Glioma Therapy.
    Yuan Chen, Zhao Lou, Yuteng Chu, Junhao Pan, Ruibing Yu, Dechun Yang, Xuanrong Sun, Xiaobao Bi.
      Human heavy-chain ferritin (FTn) that can bind to transferrin receptor 1 (TfR1) has emerged as a promising platform for brain tumor drug delivery. However, the broad expression of TfR1 in normal tissues fundamentally limits tumor selectivity and therapeutic precision. Herein, we engineered a dual-receptor-targeting FTn nanoplatform by site-specifically conjugating an epidermal growth factor receptor (EGFR) affibody to FTn using the SpyCatcher/SpyTag system, generating FTn-EGFRAfb nanoparticles. This modular strategy preserves FTn architecture and stability while enabling precise ligand conjugation. Doxorubicin (DOX) was efficiently encapsulated via temperature-controlled loading to obtain DOX@FTn-EGFRAfb with high protein recovery, pH-responsive drug release, and strong stability. In vitro, the nanoparticles showed enhanced uptake and cytotoxicity in TfR1/EGFR double-positive U87 glioma cells. In an orthotopic U87 glioma mouse model, DOX@FTn-EGFRAfb significantly inhibited tumor growth and prolonged survival without obvious systemic toxicity. This work presents a versatile protein-engineering strategy for dual-targeted glioblastoma drug delivery.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.6c00228
  46. Smart Mol. 2026 Jun;4(2): e70039
    Stepwise mitochondria-targeted photodynamic immunotherapy enabled by an outer membrane vesicles-based nanoplatform for synergistic tumor ablation and immune reprogramming.
    Xiang Cheng, Ziheng Luo, Ying Yin, Duoyang Fan, Ruyan Xie, Yanpeng Fang, Xiaohui Liu, Dayan Xiong, Wei Liu, Seraphine V Wegner, Fei Chen, Wenbin Zeng.
      Photodynamic immunotherapy (PDIT) integrates reactive oxygen species (ROS)-mediated tumor destruction with immune activation. However, its effectiveness is often hindered by tumor hypoxia, poor tumor-targeted delivery, and the immunosuppressive microenvironment. Here, we introduce BDPM@OMVs, a biomimetic nanoplatform designed to overcome these challenges. This system uses bacterial outer membrane vesicles to encapsulate a novel, heavy-atom-free aggregation-induced emission photosensitizer (BDPM). Our platform enables stepwise lysosome-to-mitochondria trafficking for enhanced PDIT. BDPM@OMVs exhibits strong near-infrared absorption and efficient intersystem crossing, leading to both Type I and Type II ROS generation, which sustains photodynamic performance even under hypoxic conditions. Upon light irradiation, BDPM@OMVs trigger photochemical internalization (PCI), disrupting lysosomes and releasing BDPM into the cytosol. The freed BDPM then selectively accumulates in mitochondria, where continues light exposure generates robust ROS, causing mitochondrial dysfunction and activating apoptosis. This process effectively amplifies tumor cell eradication. Simultaneously, BDPM@OMVs reprogram the tumor immune microenvironment by promoting macrophage repolarization from the immunosuppressive M2 to the pro-inflammatory M1 phenotype, as evidenced by upregulated TNF-α, IL-1β, and CD86 expression. In vivo studies confirm that BDPM@OMVs achieve efficient tumor accumulation, allow for real-time NIR imaging, and provide superior therapeutic outcomes. This work presents a versatile and hypoxia-resilient PDIT strategy that synergistically integrates precise subcellular photodamage with immune modulation to overcome resistance in solid tumors.
    Keywords:  bacterial outer membrane vesicles; macrophage polarization; photodynamic therapy; photosensitizers
    DOI:  https://doi.org/10.1002/smo2.70039
  47. Bioresour Technol. 2026 Jun 29. pii: S0960-8524(26)01353-2. [Epub ahead of print]459 135271
    Protein engineering combined with combinatorial optimization of critical synthetase cluster for efficient production of 1-Deoxynojirimycin in B. amyloliquefaciens.
    Xujie Li, Xin Feng, Aoying Dong, Shihao Yan, Chenshuo Zhang, Yi Rao, Zheng Zhang, Hui Tian, Dongbo Cai, Shouwen Chen.
      1-Deoxynojirimycin (1-DNJ) is a potent α-glucosidase inhibitor and a highly promising next-generation hypoglycemic agent, however, the catalytic efficiencies of its critical synthetases GabT1, YktC1 and GutB1 (TYB) are relatively low, which severely limits its large-scale production, and this research aimed to establish a cost-effective microbial cell factory for 1-DNJ production by integrating protein and metabolic engineering. Firstly, the ancestral sequence of aminotransferase GabT1 was reconstructed and engineered, and the optimal double-mutant zxGabT1DM1 showed a 52.23% elevation of relative activity compared to native GabT1. Adopting the similar strategy, the activities of double mutants YktC1DM and GutB1DM were elevated by 126.68% and 54.63%, respectively. When the optimal synthetases (zxGabT1DM1, YktC1DM and GutB1DM) were co-expressed in the strain HD19, the yield of 93.45 mg/L 1-DNJ was obtained, which was 32.81% higher than that of control strain HD18. Then, the engineered MTYB fusion protein was spatially organized by the CipA protein scaffold, and 1-DNJ yield reached 172.53 mg/L. Moreover, endogenous alkaline protease aprE gene was overexpressed to achieve efficient biotransformation of agro-industrial by-product peanut meal (PM), and 2.15 g/L 1-DNJ was acquired using the constructed strain HD29 in a 5 L fermenter, which was the highest 1-DNJ yield reported for a metabolically engineered strain to date. Collectively, this work not only establishes a green and sustainable biotechnological platform for 1-DNJ efficient production, but also opens up a promising avenue for valorizing agro-industrial by-product PM.
    Keywords:  1–Deoxynojirimycin; B. amyloliquefaciens; Greenand sustainable biotechnology; Microbialcellfactory; Proteinengineering
    DOI:  https://doi.org/10.1016/j.biortech.2026.135271
  48. ACS Sens. 2026 Jun 30.
    Engineering Guide RNAs for CRISPR-Based Biosensors.
    Xiaojing Liu, Tingyi Chen, Xiangjun Li, Qianqian Li, Guangrong Zou, Weiwen Fan, Chaoxing Liu.
      CRISPR-Cas systems, with their programmable nucleic acid-targeting capabilities, represent an ideal platform for constructing next-generation, highly sensitive biosensors. However, the clinical translation of these platforms is hindered by key limitations inherent to native single-guide RNAs (sgRNAs), including insufficient stability, potential immunogenicity, and off-target effects. To address these challenges, engineering sgRNAs has emerged as a central strategy to overcome such barriers and enhance overall biosensor performance. In this review, we provide a systematic overview of the field, beginning with the classification, molecular mechanisms, and structural features of representative CRISPR-Cas effector proteins to establish their foundational role as sensing elements. We then examine the specific limitations of native sgRNAs in biosensing applications. Building on this analysis, we highlight recent advances in sgRNA engineering strategies, which encompass three major approaches, including chemical modifications, structural remodeling, and modular functional integration. Furthermore, we review the integration of these engineered sgRNAs into advanced biosensor platforms, including microfluidic paper-based devices, centrifugal platforms, wearable patches, microneedles, and point-of-care testing (POCT) systems, and present a comparative table summarizing their performance in terms of detection signals, limits of detection, and other key metrics. Finally, we discuss persistent challenges such as the fine control of off-target effects, in vivo delivery bottlenecks, and system robustness in complex environments, and outline future directions toward amplification-free, multiplexed, and clinically translatable CRISPR-based biosensors. Overall, the engineering of sgRNAs offers a powerful means to systematically enhance the stability, specificity, and reliability of CRISPR-based biosensors, thereby accelerating their practical deployment in clinical diagnostics.
    Keywords:  CRISPR-Cas system; biosensors; clinical diagnostics; engineered sgRNA; microfluidic biosensors; non-canonical nucleic acid modifications; point-of-care Testing; wearable biosensors
    DOI:  https://doi.org/10.1021/acssensors.6c01763
  49. Biomater Adv. 2026 Jun 19. pii: S2772-9508(26)00325-0. [Epub ahead of print]188 215027
    A celastrol derivative-based multifunctional nanozyme for oxidative stress scavenging and lipid metabolism regulation in metabolic dysfunction-associated steatotic liver disease.
    Haoran Yang, Xue Cui, Kun Yu, Zhiwen Zhao, Longlong Jin, Qing Wang, Huiying Yang, Xinwei Li, Xuzhu Gao, Xianfu Wu.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive hepatic lipid accumulation accompanied by persistent oxidative stress, posing a major challenge for effective therapeutic intervention. Here, we report a multifunctional nanozyme-based therapeutic platform, MIL@Cel-6-10/ASGR1 (MCA), designed to simultaneously address this issue through coordinated hepatocyte targeting, reactive oxygen species (ROS) scavenging, and lipid metabolism regulation. MCA is constructed from a Fe/Cu-based MIL-NH2 metal-organic framework (MOF) with intrinsic superoxide dismutase- and catalase-like activities, encapsulating a rationally engineered Celastrol derivative (Cel-6-10) for enhanced anti-inflammatory efficacy and stability. Surface conjugation an anti-asialoglycoprotein receptor 1 (ASGR1) monoclonal antibody confers hepatocyte-targeting capability and simultaneously activates liver X receptor alpha (LXRα), thereby promoting hepatic lipid efflux. In vitro, MCA effectively attenuates palmitate-induced hepatocyte lipotoxicity by reducing oxidative stress, suppressing apoptosis, and limiting lipid accumulation. In a diet-induced murine model of MASLD, MCA demonstrates pronounced liver accumulation, markedly ameliorates hepatic steatosis, improves serum lipid profiles, and reduces liver injury markers without detectable systemic toxicity. Transcriptomic analysis reveals extensive hepatic reprogramming, characterized by suppression of pro-steatotic and pro-inflammatory pathways and enhancement of antioxidant and metabolic homeostatic programs. Collectively, this work presents a Celastrol derivative-integrated nanozyme strategy as an effective materials-based approach for MASLD management.
    Keywords:  Celastrol derivative; Hepatic steatosis; MIL-NH(2) MOF; Multi-functional nanozyme; Synergistic therapy
    DOI:  https://doi.org/10.1016/j.bioadv.2026.215027
  50. ACS Appl Bio Mater. 2026 Jul 03.
    Therapeutic Vaccines Based on Iron-Coordinated Metal-Phenolic Networks for Eradicating Drug-Resistant Staphylococcus aureus.
    Hao Sun, Suke Liu, Yijun Gu, Liling Xie, Mingchun Li, Qilin Yu.
      Drug-resistant Staphylococcus aureus (DRSA) infections present a formidable therapeutic challenge severely threatening human health. To address this, we engineered a metal-phenolic network (MPN) platform that co-immobilizes whole-cell DRSA with immunostimulatory metal ions (i.e., Fe3+, Mn2+, Zn2+) under mild conditions. Among these, the iron-coordinated MPN (SA@FeMPN) exhibited superior potency, leveraging a dynamic valence transition mechanism to robustly amplify the TLR2/NF-κB signaling. This mechanism promoted functional polarization of macrophages to the M1 state and drove dendritic cell maturation. In a murine systemic infection model, SA@FeMPN elicited robust cellular and humoral immunity, achieving a 2-18-fold greater reduction in bacterial burden across major organs compared to other MPNs, and established durable immunological memory to prevent infection relapse. Collectively, this work establishes iron-coordinated MPNs as a rational design platform for next-generation immunotherapy and identifies SA@FeMPN as a promising therapeutic vaccine candidate that not only eradicates established DRSA infections but also confers lasting protection against recurrence.
    Keywords:  drug-resistant Staphylococcus aureus; metal immunotherapy; metal−phenolic network; signaling pathway; therapeutic vaccine
    DOI:  https://doi.org/10.1021/acsabm.6c00576
  51. AAPS PharmSciTech. 2026 Jul 02. pii: 250. [Epub ahead of print]27(5):
    The Preparation and Physicochemical Characterization of a Triple Synergistic Nanoplatform Designed for Targeted Subcutaneous Delivery of Sitagliptin with Potential for β-Cell Preservation.
    Mo'tasem M Alsmadi, Rana Obaidat.
      Effective diabetes management necessitates innovative strategies that simultaneously stimulate β-cell growth and prevent apoptosis. While sitagliptin is an established therapeutic, its clinical utility is often hampered by suboptimal oral bioavailability and a lack of site-specific delivery. This research details the development and in vitro assessment of Sita-Ex-Cs-SeNPs, a subcutaneous nanocarrier composed of sitagliptin-loaded chitosan-selenium nanoparticles conjugated with exenatide. The platform is engineered to leverage GLP-1 receptor affinity for pancreatic targeting and utilize selenium's intrinsic antioxidant properties to achieve therapeutic synergy. We employed the ionotropic gelation technique to encapsulate sitagliptin and integrate exenatide and selenium into a unified, stable delivery system. The resulting nanoparticles exhibited a spherical architecture with an average diameter of 314.1 nm and a zeta potential of + 18.7 mV. We achieved a high encapsulation efficiency of 98%. Analytical techniques (DSC and PXRD) confirmed that sitagliptin transitioned to an amorphous state, while FTIR validated successful peptide conjugation. Release kinetics followed the Weibull model, demonstrating a controlled biphasic profile (57% over 24 h) that significantly extends the therapeutic window compared to the free drug. Sita-Ex-Cs-SeNPs offer a promising, biocompatible approach for targeted diabetes intervention. Although in vitro results confirm stable sustained release, subsequent in vivo trials are essential to validate their efficacy in β-cell preservation.
    Keywords:  Chitosan-selenium nanoparticles; Exenatide; Sitagliptin; Targeted Diabetes Nanocarrier; β-cell preservation
    DOI:  https://doi.org/10.1208/s12249-026-03489-1
  52. Chem Sci. 2026 Jun 22.
    Engineering asymmetric solvation structures for synergistically boosted quasi-solid thermocells.
    Wentao Lin, Shuo Niu, Shukai Wu, Chao Fang.
      Quasi solid-state thermocells (QTECs) based on the thermogalvanic effect offer a promising route for directly converting abundant low-grade heat into electricity. Introducing a single solvent into hydrogel electrolytes, a common strategy to enhance thermopower, often yields a marginal solvation entropy difference between redox ions and provides limited gains in ion transport. To break this longstanding trade-off, we present a simple yet highly effective co-solvent strategy that employs trimethyl phosphate and ethylene glycol to construct hybrid hydrogel electrolytes. This approach synergistically enlarges solvation entropy differences of redox ions, amplifies the concentration gradient across the thermocell, and enhances redox ion transport through the hydrogel network. The resulting hydrogel electrolyte achieves superior thermoelectrochemical performance and demonstrates efficient harvesting of low-grade heat even at sub-zero temperatures. Advanced characterization techniques, integrated with molecular simulations, elucidate that the enhanced thermoelectrochemical performance originates from co-solvent engineered asymmetric solvation structures. This work demonstrates targeted, additive-free modulation of the solvation environment in thermogalvanic hydrogels as a practical strategy to significantly enhance thermoelectrochemical performance.
    DOI:  https://doi.org/10.1039/d6sc03942a
  53. Biomed Pharmacother. 2026 Jul 01. pii: S0753-3322(26)00739-0. [Epub ahead of print]201 119703
    Targeted attenuation of liver fibrosis using microbubble-enhanced protease-activated receptor 1 chimeric antigen receptor T cells.
    Hao-Chien Hung, Ainani Priza Minhalina, Po-Jung Hsu, Ke-Hung Tsui, Ting-Yen Chao, Chao Lien Liu.
       BACKGROUND: Liver diseases account for a significant global mortality rate, with hepatic fibrosis representing a critical precursor to cirrhosis and liver cancer. Current therapeutic options remain limited, as no antifibrotic drugs have received FDA approval. In this study, we propose a novel CAR-T cell strategy targeting protease-activated receptor 1 (PAR1) on activated hepatic stellate cells (aHSCs) to combat liver fibrosis.
    METHODS: By engineering CAR-T cells specifically against PAR1, we aimed to selectively eliminate PAR1-expressing HSCs and thereby inhibit PAR1-dependent fibrogenesis. To enhance CAR-T cell delivery into the fibrotic liver microenvironment, we employed ultrasound-mediated delivery with microbubbles (USMB) in a Carbon tetrachloride (CCl4)-induced liver fibrosis mouse model.
    FINDINGS: Our results demonstrated that PAR1CAR-T cells effectively eliminated PAR1-expressing HSCs in vitro. In animals, USMB significantly enhanced CAR-T cell penetration, migration, and intrahepatic retention within the fibrotic liver microenvironment. Blockade of PAR1 signaling suppressed HSC activation, attenuated fibrogenesis, and reduced fibrosis progression. Mechanistically, activation of the TGF-β/p-SMAD2/3 axis was accompanied by upregulation of PAR1 on activated HSCs, and this fibrogenic axis was attenuated by the targeted elimination of PAR1-expressing HSCs.
    INTERPRETATION: Collectively, USMB-mediated PAR1CAR-T cell therapy demonstrated potent antifibrotic efficacy by enhancing CAR-T cell delivery and intrahepatic retention in the liver, offering a promising antifibrotic immunotherapy approach for patients with liver fibrosis.
    Keywords:  Activated hepatic stellate cells (aHSCs); Chimeric antigen receptor (CAR)-T cell; Liver fibrosis; Protease-activated receptor 1 (PAR1); Ultrasound-mediated delivery with microbubbles (USMB)
    DOI:  https://doi.org/10.1016/j.biopha.2026.119703
  54. J Ind Microbiol Biotechnol. 2026 Jun 27. pii: kuag018. [Epub ahead of print]
    Engineering Escherichia coli to produce medium chain oleochemicals from C2 substrates.
    Sri Harsha Adusumilli, Shivangi Mishra, Brian F Pfleger.
      Many strategies to create a circular bioeconomy have been proposed. To be successful, CO2 must be reduced with renewable energy into chemical building blocks, from which the chemical industry can be supported. Circular strategies include leveraging photosynthesis to produce sugar and lipid intermediates or renewable electricity to produce hydrogen or other electron carriers to support CO2 reduction. Acetogens can anaerobically reduce CO2 with H2 to produce mixtures of small organic molecules in gas fermentations. We previously demonstrated that acetate, a common product of gas fermentation, can be converted to the model oleochemical dodecanol in engineered Escherichia coli. Here, we explored the conversion of ethanol and mixtures of ethanol and acetate to the same model oleochemicals. Co-feeding ethanol can supply both carbon and additional reducing power relative to acetate alone. In this work, we engineered E. coli to catabolize ethanol and expressed two distinct ethanol metabolism pathways in different operons and combined them with improved engineered acetate activation. We evaluated the performance of these operons in dodecanol-producing strains when fed ethanol or acetate and found ethanol to be a better carbon source when judged by product titers. The engineered strains fed ethanol produced about 2-fold more dodecanol than the strains fed acetate. This increase was in part, due to change in product distribution. Cells fed ethanol produced predominantly dodecanol, whereas cells fed acetate generated a mixture of dodecanol and dodecanoic acid. Dodecanol titers were further improved by employing feeding strategies in controlled bioreactors.
    Keywords:   Escherichia coli ; Ethanol utilization; Fatty alcohols; Redox balance; Substrate optimization
    DOI:  https://doi.org/10.1093/jimb/kuag018
  55. J Drug Target. 2026 Jul 02. 1-22
    Galactosylated chitosan-functionalized liposome for targeted delivery of Coreopsis tinctoria flavonoids: Protective effect in acute liver injury.
    Juan Du, Xinmei Chen.
      Acute liver injury (ALI) is a syndrome characterized by rapid deterioration of liver function, rapid progression, and high mortality. In this study, a liver-targeted drug delivery system, galactosylated chitosan modified Coreopsis tinctoria flavonoid liposome (GC-CTF-Lip) was constructed. The targeted ligand was synthesized by the amidation reaction between chitosan and lactobionic acid, and its structure was identified. The modification conditions of GC on liposomes were optimized and characterization of liposomes was studied. The liver-targeting ability of GC-CTF-Lip was evaluated through in vivo and in vitro experiments. A mouse model of ALI induced by CCl4 was established to evaluate the hepatoprotective effect of GC-CTF-Lip. The results confirmed that lactobionic acid was successfully grafted onto chitosan. Finally, GC-CTF-Lip with particle size of 236.32 ± 0.60 nm and encapsulation efficiency of 68.67 ± 0.58% was obtained. GC-CTF-Lip improved the uptake efficiency of CTF in hepatocytes in vitro and exhibited excellent liver enrichment in vivo. Serum ALT/AST levels were significantly decreased, and the histological liver injury was alleviated. It exhibited a trend of liver enrichment and a hepatoprotective effect. This liver-targeted nanodrug delivery system can achieve active accumulation of drugs at the lesion site, providing a potential strategy for the prevention of ALI.
    Keywords:  Acute liver injury; Asialoglycoprotein receptor; Galactosylated chitosan; Liposome; Liver targeting
    DOI:  https://doi.org/10.1080/1061186X.2026.2698820
  56. Int J Nanomedicine. 2026 ;21 585900
    PEG-NH2-Modified Gold Nanoparticle Deliver miRNA-140 for Effective Treatment of Osteoarthritis.
    Xiangping Luo, Xiaochun Jiang, Zheng Kang.
       Background: Osteoarthritis is a prevalent disease that causes pain and disability in older adults. MicroRNA-140 (miR-140) emerges as a promising therapeutic agent as it suppresses cartilage-degrading enzymes (eg, ADAMTS5, MMPs). However, its clinical translation is limited by rapid intra-articular degradation and poor chondrocyte penetration. The purpose of this experiment was to construct a nanocarrier for delivering miR-140 into chondrocytes, and to detect its delivery efficiency and biological effects.
    Methods: We engineered polyethylene glycol-aminated gold nanoparticles (AuNPs-PEG-NH2) for miR-140 delivery. The efficiency of AuNPs-PEG-NH2-mediated miR-140-5p (AuNPs-miR-140) delivery was assessed by fluorescence microscopy and flow cytometry. The biological function of AuNPs-miR-140 complexes was detected by quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, and enzyme-linked immunosorbent assay. The effect of AuNPs-miR-140 in attenuating osteoarthritis progression was tested in a mouse model.
    Results: Fluorescence microscopy and flow cytometry revealed efficient delivery of miR-140-5p into ATDC5 cells by AuNPs-PEG-NH2. RT-qPCR analysis demonstrated a controlled sustained release of miR-140-5p from the nanocarriers, maintaining elevated miR-140-5p levels for 14 days. In vitro, AuNPs-miR-140 significantly suppressed catabolic factors (MMP-13 and ADAMTS5; p<0.01) and upregulated anabolic markers (COL2 and ACAN; p<0.01) in IL-1β-stimulated chondrocytes. Consistent with these findings, in vivo studies showed that AuNPs-miR-140 significantly attenuated cartilage degradation in mice with osteoarthritis, and preserved cartilage structural integrity.
    Conclusion: AuNPs-PEG-NH2 is an efficient intra-articular miRNA delivery platform that successfully overcame the critical limitations of free miRNA therapy. This system effectively restored cartilage homeostasis and delayed osteoarthritis progression by prolonging miR-140 bioactivity and promoting chondrocyte uptake.
    Keywords:  cartilage; gold nanoparticles; microRNA; osteoarthritis
    DOI:  https://doi.org/10.2147/IJN.S585900
  57. J Nanobiotechnology. 2026 Jun 30.
    Neutrophil membrane-mediated biomimetic nanoparticle for co-delivery of icariin and siORMDL3 attenuates asthma exacerbated by respiratory syncytial virus.
    Xudong Zhang, Ting Luan, Chenyu Zhao, Li Chen, Fei Wang, Qi Cheng, Tong Zhu, Wanjie Huang.
       BACKGROUND: Asthma is a chronic inflammatory disorder, and respiratory syncytial virus (RSV) is a major trigger of asthma exacerbation. This study aimed to improve therapeutic efficacy against RSV-exacerbated asthma using neutrophil membrane (NM)-coated nanoparticles (NPs) for co-delivery of orosomucoid-like 3 (ORMDL3)-targeting small interfering RNA (siRNA) and icariin.
    METHODS: A biomimetic dual-drug delivery system (ORMDL3-targeting siRNA [siORMDL3]/Icariin NPs@NM) was developed by coating NM onto poly(lactic-co-glycolic acid) NPs co-loaded with icariin and siORMDL3. The physicochemical properties, biosafety, cellular uptake, biodistribution behavior, and RNA interference efficiency of the NPs were evaluated. Their therapeutic efficacy was further assessed in vitro and in vivo.
    RESULTS: The siORMDL3/Icariin NPs@NM exhibited a core-shell structure with NM camouflage, an average diameter of 141.1 nm, and a negatively charged surface. The NPs demonstrated enhanced lung-targeting delivery efficiency with no apparent adverse effects. In vitro, siORMDL3/Icariin NPs@NM significantly improved the viability of BEAS-2B cells treated with interleukin-4 and RSV, while markedly reducing inflammatory cytokine production and oxidative stress markers. In vivo, the siORMDL3/Icariin NPs@NM effectively alleviated airway resistance and improved the inflammatory microenvironment in mice with RSV-exacerbated asthma, with no observable toxicity in major organs.
    CONCLUSION: siORMDL3/Icariin NPs@NM demonstrated potent anti-inflammatory and antioxidative effects and may serve as an effective dual-drug delivery platform for the treatment of RSV-exacerbated asthma through combination therapy.
    Keywords:  Biomimetic nanoparticle; Icariin; Neutrophil membrane; ORMDL3 siRNA; Respiratory syncytial virus-exacerbated asthma; Targeted therapy
    DOI:  https://doi.org/10.1186/s12951-026-04726-2
  58. J Control Release. 2026 Jun 30. pii: S0168-3659(26)00546-8. [Epub ahead of print] 115143
    Bio-recruiting hydrogel targeting mitochondrial homeostasis under neutrophil extracellular traps for diabetic wound repair.
    Junying Song, Binyu Song, Yuhan Zhu, Yifu Zhu, Yufei Zhang, Yajuan Song, Tong Wang, Yi Shi, Yan Jiao, Guodong Yang, Zhou Yu, Baoqiang Song.
      Diabetic wound healing is a complex process that requires precise coordination among functional cells, with endothelial cells (ECs) playing a critical role in tissue vascularization. We begin by identifying neutrophil extracellular traps (NETs) as one of critical stressors that disrupts mitochondrial homeostasis in ECs. In addition, inadequate recruitment of ECs often leads to unsatisfactory regenerative outcomes. To address these issues, we developed a composite hydrogel formulation co-encapsulating C-X-C motif chemokine ligand 12 (CXCL12) mRNA-loaded exosomes to promote pro-regenerative endothelial cell homing, and leonurine (Leo) to regulate cellular functionalities, thereby preserving endothelial function essential for neovascularization. By pairing exosomal mRNA delivery with the MS2 coat protein (MCP)-MS2 tethering system for mRNA payload multiplication, we achieved sustained CXCL12 production and cascade-amplified recruitment of CXCR4-positive cells. Moreover, Leo released from the composite hydrogel protectively rescued mitochondrial dysfunction. Further, application of this hydrogel to full-thickness skin defects led to significantly improved wound regeneration in diabetic mice. In summary, this study establishes a therapeutic "recruit-reinforce" platform based on a dual-delivery hydrogel armed with CXCL12 mRNA-enriched exosomes and Leo, thereby precisely targeting mitochondrial homeostasis under NETs stress for efficient diabetic wound repair.
    Keywords:  CXCL12; Exosomes; Hydrogel; Leonurine; Mitochondrial homeostasis; Neutrophil extracellular traps
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115143
  59. J Control Release. 2026 Jul 01. pii: S0168-3659(26)00555-9. [Epub ahead of print] 115152
    Selective silencing of placental anti-angiogenic factors in invasive trophoblasts via membrane-fusion divalent siRNA delivery for preeclampsia therapy.
    Wenqiang Qian, Ying Zhang, Yao Yao, Xiaojun Zhu, Dongli Sun, Huidi Jiang, Peiyue Jiang, Jiaxin Shang, Weidong Fei, Caihong Zheng.
      Preeclampsia is a common and severe hypertensive disorder of pregnancy driven by placental dysfunction. In the absence of effective therapies, termination of pregnancy remains the only definitive treatment, resulting in significant maternal and fetal mortality. In this study, single-cell transcriptomic analysis of human placentae identified extravillous trophoblasts as a key pathogenic invasive cell subtype in preeclampsia, characterized by aberrant overexpression of fms-like tyrosine kinase-1 (Flt-1) and endoglin (Eng), the molecular sources of the soluble anti-angiogenic factors sFlt-1 and sEng. To coordinately modulate these pathogenic mediators, this study designed a novel dual-target divalent siRNA (dual-siRNA) to enhance molecular stability and enable simultaneous gene silencing, and further developed a ligand-functionalized membrane-fusogenic liposomal delivery system (iMFlip) targeting receptors highly expressed in invasive trophoblasts for selective dual-siRNA delivery. The optimized iMFlip@dual-siRNA exhibited favorable stability and low protein adsorption properties, and achieved efficient cytosolic siRNA delivery predominantly through membrane fusion, thereby substantially bypassing lysosomal degradation. In vitro, iMFlip@dual-siRNA markedly restored the invasion, migration and angiogenesis of hypoxia-injured HTR-8/SVneo cells. The subsequent pharmacodynamic studies showed that iMFlip@dual-siRNA simultaneously reduced circulating maternal sFlt-1 and sEng levels, alleviated placental vascular dysfunction and inflammatory microenvironment remodeling through reactivation of the PI3K/Akt/eNOS signaling pathway, and consequently improved maternal hypertension, proteinuria, and fetal growth restriction in a preeclamptic mouse model. Collectively, this study established a mechanism-driven therapeutic paradigm that integrated single-cell transcriptomic analysis-guided pathogenic target identification with advanced nucleic acid delivery strategies, offering a promising precision intervention approach for preeclampsia.
    Keywords:  Anti-angiogenic factors; Divalent siRNA; Invasive trophoblasts; Membrane fusion; Preeclampsia; Single-cell transcriptomic
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115152
  60. Theranostics. 2026 ;16(13): 7088-7107
    Ultrasound targeted fatty acid nitroalkene-containing lipid nanoparticles attenuate inflammation and reverse myocardial fibrosis.
    Muhammad W Amjad, Soheb A Mohammed, Marco Fazzari, Xucai Chen, Bruce A Freeman, Terry O Matsunaga, Yijen L Wu, Sean Hartwick, Thomas Becker-Szurszewski, Devin R E Cortes, John J Pacella.
       Rationale: Myocardial ischemia-reperfusion injury (MIRI) induces oxidative stress and inflammatory signaling that drive fibroblast activation, myocardial fibrosis, and progressive cardiac dysfunction, for which effective targeted therapies remain limited. The electrophilic fatty acid nitroalkene 10-nitro-octadec-9-enoic acid (NO₂-FA) exhibits anti-inflammatory and antifibrotic properties but pharmacological actions have been limited by extents of myocardial delivery. Ultrasound-targeted cavitation (UTC) using lipid-shelled gas-filled nanoparticles (LNPs) enables spatially controlled drug release and represents a promising theranostic strategy.
    Methods: NO₂-FA were incorporated in LNPs and delivered focally to the myocardium using UTC. Therapeutic efficacy was evaluated in rodent models of MIRI and myocardial fibrosis. In the MIRI model, animals received UTC + NO₂-FA LNPs, intravenous NO₂-FA, or sham treatment. Cardiac structure, function, and molecular remodeling were assessed using echocardiography, histological staining, polymerase chain reaction, and enzyme-linked immunosorbent assay. In the myocardial fibrosis model, additional analyses included immunohistochemistry and cardiovascular magnetic resonance imaging.
    Results: UTC-mediated delivery of NO₂-FA LNPs significantly reduced myocardial fibrosis compared with intravenous NO₂-FA (p = 0.03) and sham treatment (p = 0.001), as demonstrated by histological quantification and reduced late gadolinium enhancement. Targeted NO₂-FA delivery also improved cardiac output and favorably modulated molecular markers associated with fibrosis and inflammation. Across both experimental models, UTC-facilitated NO₂-FA delivery consistently demonstrated superior therapeutic efficacy relative to non-targeted administration.
    Conclusions: Spatially targeted delivery of NO₂-FA using ultrasound-mediated cavitation enhances cardioprotective and antifibrotic effects in experimental models of MIRI and myocardial fibrosis. This platform integrates targeted therapy with imaging-based assessment and supports further development of UTC-enabled theranostic approaches for ischemic heart disease.
    Keywords:  fatty acid nitroalkenes; lipid nanoparticles; myocardial fibrosis; myocardial ischemia-reperfusion injury; ultrasound-targeted cavitation
    DOI:  https://doi.org/10.7150/thno.126503
  61. Transl Res. 2026 Jun 28. pii: S1931-5244(26)00139-8. [Epub ahead of print]
    Extracellular Vesicles in the Tumor Microenvironment: Diverse Origins, Multifaceted Functions, and Emerging Therapeutic Opportunities.
    Zhanghao Li, Jinfang Zhang, Huiyi Guan, Wei Yang, Wing Ho Chan, Nanxi Li, Chuanxin Zhong, Ge Zhang, Sifan Yu, Aiping Lyu, Jin Liu.
      As pivotal mediators in the tumor microenvironment (TME), extracellular vesicles (EVs) orchestrate intercellular communication by transferring bioactive cargo, including proteins, lipids, and nucleic acids. These highly heterogeneous EVs can exert profoundly divergent impacts on malignant progression and clinical treatment outcomes. Beyond their intrinsic biological roles, their natural capacity for cargo transfer also supports their development as next-generation engineered delivery platforms. Furthermore, specific subtypes of EVs or those carrying particular cargo are being pursued as both therapeutic targets for modulating pathogenic signaling and as noninvasive biomarkers for diagnosis and prognosis. Although modulation of EV-mediated pathways has shown promise in preclinical models, clinical translation remains hindered by insufficient target selectivity, off-target effects, and challenges in achieving scalable, standardized manufacturing. This review synthesizes current knowledge on EV heterogeneity and their diverse functions in modulating the TME, and further outlines a framework for emerging applications in clinical diagnostics and therapeutics.
    Keywords:  Engineered extracellular vesicles; Extracellular vesicle; Small molecule inhibitor; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trsl.2026.06.021
  62. Facial Plast Surg Clin North Am. 2026 Aug;pii: S1064-7406(26)00036-2. [Epub ahead of print]34(3): 347-363
    Exosomes in Cutaneous Wound Healing and Facial Skin Regeneration: Clinical and Translational Perspectives.
    Jeffrey Janus, Jieun Lee, Allison Pontius.
      Exosomes-small extracellular vesicles containing protein, lipid, and nucleic-acid cargo-modulate key pathways involved in inflammation, angiogenesis, and extracellular matrix remodeling. This narrative review synthesizes current pre-clinical and clinical evidence supporting exosome-based interventions in cutaneous wound healing and facial skin regeneration, with attention to delivery strategies, translational limitations, and regulatory considerations relevant to facial plastic and reconstructive surgery. Across multiple in vivo models, exosome-based therapies have been associated with accelerated wound closure, enhanced neovascularization, and more organized collagen architecture, with attenuation of excessive fibrotic remodeling in later phases of healing.
    Keywords:  Exosome; Extracellular vesicle; Plastic surgery; Skin aging; Skin rejuvenation; Wound healing
    DOI:  https://doi.org/10.1016/j.fsc.2026.05.001
  63. bioRxiv. 2026 Jun 26. pii: 2026.06.25.734611. [Epub ahead of print]
    Expression-linked promoter selection (ELiPS) engineers short, strong ubiquitous promoters for gene therapy applications.
    Sydney V Oraskovich, Kazuomori K Lewis, Joost van Haasteren, Hyuncheol Lee, Esther Chu, David V Schaffer.
      Adeno-associated virus (AAV)-based gene therapy has made steady progress towards efficient delivery to numerous target cell populations, yet the virus's 5 kb packaging limit remains a challenge for effective and in some cases cell-selective cargo expression. Here, we introduce Expression-Linked Promoter Selection (ELiPS), a high-throughput platform for generating and functionally screening >10 6 engineered, short promoter variants using an AAV expression platform. ELiPS relies on a Golden Gate cloning method to build random oligomers of selected transcription factor binding sites (TFBSs) upstream of a minimal promoter, GFP, and a unique 3' barcode. As a proof of concept, to engineer short (∼250 bp), synthetic, ubiquitous promoters, we applied ELiPS to build two libraries composed of TFBSs for ubiquitously expressed transcription factors (TFs) and screened them via AAV-mediated transduction in vitro . This strategy identified promoters with expression surpassing human cytomegalovirus (CMV) and CAG in vitro , and one variant was capable of driving therapeutic expression of B-domain-deleted Factor VIII (BDDFVIII) in vivo at levels comparable to a liver-specific promoter benchmark. ELiPS thus establishes a scalable framework for promoter discovery, enabling the design of compact, ubiquitous or cell-selective expression cassettes that enable further precision and efficacy in AAV-based gene therapies.
    DOI:  https://doi.org/10.64898/2026.06.25.734611
  64. Mater Today Bio. 2026 Aug;39 103374
    Shattering the "golden armor": A natural supramolecular nanoplatform for optical virulence modulation and MRSA keratitis therapy.
    Zhi-Heng Yang, Hong-Miao Dang, Xiao Zhang, Ling-Feng Xu, Lu-Lu Wang, Xin Pang, You-Hong Hu.
      Methicillin-resistant Staphylococcus aureus (MRSA) keratitis constitutes a formidable therapeutic impasse, driven by the convergence of the pathogen's intrinsic antioxidant "golden armor" (staphyloxanthin, STX) and the cornea's extrinsic physical barrier. Herein, we overcome these dual obstacles via carrier-free supramolecular nanotherapeutic (HB@GA), engineered through the co-assembly of the natural photosensitizer hypocrellin B (HB) and the bioactive glycyrrhizic acid (GA). This minimalist all-active design not only ensures 100% active payload but also enables deep corneal drug delivery via GA-enhanced membrane permeation. Upon 460 nm irradiation, the system executes a synchronous disarm-and-kill cascade, where the wavelength-specific photobleaching of STX optically strips the bacterial antioxidant defense, rendering the pathogen hypersensitive to concurrent reactive oxygen species storm generated by HB. Beyond potent sterilization, the bioactive GA component fundamentally reshapes the inflammatory microenvironment by inhibiting the HMGB1/TLR4 signaling axis, which shifts macrophage polarization from a pro-inflammatory M1 to a tissue-reparative M2 phenotype. In a murine keratitis model, the HB@GA nanoplatform combined with light treatment achieved rapid bacterial clearance and accelerated corneal reconstruction. By seamlessly integrating optical bio-intervention with bioactive supramolecular nanomedicine, this work establishes a promising "anti-infection and pro-repair" paradigm for addressing multidrug-resistant ocular pathologies.
    Keywords:  Corneal penetration; Methicillin-resistant Staphylococcus aureus keratitis; Optical intervention; Photodynamic therapy; Staphyloxanthin; Supramolecular co-assembly
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103374
  65. J Exp Orthop. 2026 Jul;13(3): e70825
    Exosomes from mesenchymal stem/stromal cells and their therapeutic role in osteoarthritic pain.
    Dimitrios Kouroupis, Stanislava Jergova, Jacqueline Sagen, Thomas M Best.
      
    Keywords:  calcitonin gene‐related peptide; exosomes; mesenchymal stem/stromal cells; osteoarthritic pain; substance P
    DOI:  https://doi.org/10.1002/jeo2.70825
  66. Res Sq. 2026 Jun 18. pii: rs.3.rs-9901177. [Epub ahead of print]
    Dual-functional Nanocarrier for Improved Immunochemotherapy of Acute Myeloid Leukemia.
    Song Li, Zhuoya Wan, Limei Wu, Yiqing Mu, Bei Zhang, Jing-Zhou Hou, Jingjing Sun, Wei Du.
      Advances with the 7 + 3 regimen and liposomal CPX-351 have significantly improved the treatment of acute myeloid leukemia (AML); however, challenges like drug resistance and immune evasion persist. Despite the demonstrated potential of immunotherapy in treating several types of solid tumors, its impact on the treatment of AML remains limited. To address these challenges, we engineered an ultrasmall (~ 15 nm) cytarabine (AraC)-based polymeric micelle nanocarrier (PAraC) for efficient AML cell uptake and bone marrow niche targeting. scRNA-seq and real-world dataset analysis identified upregulated TLR7/8 in malignant AML cells, particularly after 7 + 3 treatment, supporting the inclusion of the TLR7/8 agonist R848 in our combination therapy. Our strategy integrates smart co-delivery of AraC, daunorubicin (Daun), and R848 using the PAraC platform. This triple nano-combination (PAraC/Daun/R848) demonstrated potent antitumor efficacy, outperforming CPX-351 and PAraC/Daun in multiple leukemia models, including murine and patient-derived xenografts (PDX) AML models and AraC-resistant acute lymphoblastic leukemia (ALL) model. Notably, PAraC/Daun/R848 reversed immunosuppressive phenotypes seen with CPX-351 or PAraC/Daun and induced robust leukemia cell maturation. With its modular design, efficient delivery, and remarkable preclinical performance, the PAraC platform holds immense promise for clinical translation, offering a new frontier for immunotherapeutic interventions in AML.
    DOI:  https://doi.org/10.21203/rs.3.rs-9901177/v1
  67. Bioact Mater. 2026 Nov;65 777-795
    Spatiotemporal delivery of exosomes and alendronate orchestrates osteoblastic and osteoclastic activity for osteoporotic bone regeneration.
    Shabnam Anjum, Mohammad Saeed, Wenjing Zhang, Taozhao Yu, Zhihua Yang, Ping Liu, Sapna Sayed, Yuhui Kou, Baoguo Jiang, Yang Zhang.
      The treatment of bone defects in osteoporotic (OP) patients remain a significant clinical challenge. The most important and challenging task is to promote sufficient bone formation in the early stage and effectively inhibit bone resorption all period of bone healing. Unfortunately, the efficacy of current strategies falls short of meeting this requirement. In this study, we developed a dual-delivery system that allows spatiotemporal release of bone marrow stem cell-derived exosomes (BMSC-Exo) and alendronate (Aln) by core-shell nanofiber to match the spatiotemporal dynamics of bone healing and effectively treat OP bone defects. Core-shell polycaprolactone/polyvinyl alcohol (P/PVA) nanofibers were fabricated through coaxial electrospinning, incorporating Aln within the core layer and BMSC-Exo functionalized onto the surface of nanofiber via chemical modification with polyethyleneimine (PEI). Physicochemical characterization confirmed the successful fabrication of PEI@P/PVA-Aln nanofibers, which exhibited excellent mechanical strength (22.77 MPa), hydrophilicity (9.66°), and enabled the spatiotemporal release of BMSC-Exo and Aln. In vitro experiments showed that Exo-PEI@P/PVA-Aln scaffold effectively promoted osteogenic differentiation by miR-486 in the BMSC-Exo through regulation of the PTEN/AKT signaling axis and significantly reduced osteoclastic differentiation. Under a rat OP cranial defect model, the Exo-PEI@P/PVA-Aln scaffold demonstrated substantially enhanced bone repair efficiency after 4 and 10 weeks. To conclude, our results showed that the dual delivery of BMSC-Exo and Aln with spatiotemporal release orchestrates osteoblastic and osteoclastic activity, providing a potential strategy to facilitate the regeneration of OP bone defects.
    Keywords:  Alendronate; Bone regeneration; Exosomes; Osteoporosis; Spatiotemporal release
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.06.019
  68. JPRAS Open. 2026 Jul;50 665-684
    Exosome therapy for flap and skin graft survival: A systematic review and meta-analysis of preclinical evidence.
    Alexander A W Perkasa-Hendropriyono, David S Perdanakusuma, Dwikora N Utomo, Budiman Budiman, Sepehr S Lajevardi, Gazi Hussain, Anand K Deva.
      Flap necrosis and graft failure remain significant sources of morbidity in reconstructive and aesthetic surgery, yet no cell-free biological adjunct has been established to improve tissue survival after transfer. Exosomes are nano-sized extracellular vesicles capable of simultaneously modulating angiogenesis, inflammation, apoptosis, and oxidative stress, and have been investigated as candidate regenerative adjuncts in plastic surgery. This PROSPERO-registered systematic review and meta-analysis (CRD420251146650), conducted per PRISMA 2020, searched PubMed, OVID, Scopus, Web of Science, and Google Scholar through September 2025 and included 24 animal studies (19 flap; 5 skin graft). Flap and graft studies were analysed as separate populations. Random-effects meta-analysis suggested increased flap survival (k = 19; MD 35.54%; 95% CI 25.11-45.97; p < 0.0001) and angiogenesis (k = 19; SMD 3.60; 95% CI 2.66-4.54; p < 0.00001). However, heterogeneity was extreme (I² 76-97%), and funnel plot asymmetry with significant Egger's tests (both p < 0.001) indicated substantial small-study effects; the true effect is likely considerably smaller than these pooled estimates suggest, which should therefore be interpreted with caution. Perfusion, VEGF expression, and apoptosis generally favoured exosomes in narrative synthesis. In skin graft models, 4 of 5 studies reported improved graft take by days 10-14, but certainty was low. Allocation concealment was unreported in all studies and blinding unclear in most, representing a major methodological limitation that may further inflate observed effects. Preclinical evidence provides a biological rationale, but findings remain exploratory and hypothesis-generating. Standardised preclinical replication is required before clinical translation can be considered.
    Keywords:  Angiogenesis; Exosome; Extracellular vesicle; Flap; Meta-Analysis; Skin graft
    DOI:  https://doi.org/10.1016/j.jpra.2026.05.042
  69. J Nanobiotechnology. 2026 Jun 30.
    CD4 + T cell-derived exosomal miR-223-3p serves as a potential biomarker for systemic lupus erythematosus and attenuates lupus nephritis in NZBWF1/J mice.
    Shu-Zhen Xu, Peng Wang, Sha-Sha Tao, Hai-Fen Wei, Yu-Tong Tan, Xiao-Xiao Li, Xiao-Ke Yang, Hui-Hui Shen, Guo-Cui Wu, Hai-Feng Pan.
      Although emerging evidence links exosomal miRNAs to autoimmunity, the specific role of CD4 + T cell-derived exosomal miRNAs in systemic lupus erythematosus (SLE) remains incompletely understood. This study aimed to identify key exosomal miRNAs derived from CD4 + T cells in SLE and to assess their diagnostic and therapeutic potential. We found that CD4 + T cell-derived exosomal miR‑223‑3p was downregulated in SLE patients and demonstrated moderate diagnostic performance (AUC = 0.71, 95% CI: 0.65-0.77). When combined with conventional clinical markers, it provided incremental diagnostic value. Its correlation with clinical markers (C3/C4) was specific to the CD4 + T cell-derived exosomal fraction, distinguishing it from the plasma‑derived counterpart. Functionally, miR-223-3p overexpression inhibited the secretion of inflammatory cytokines and T cell apoptosis while promoting mitophagy via FBXW7. Additionally, it disrupted pathological T‑B cell interactions by suppressing BAFF and CD19 expression. In a murine lupus model (NZBWF1/J), administration of exosomal miR‑223‑3p alleviated lupus nephritis, as evidenced by reduced proteinuria, lower Anti‑dsDNA titers, and diminished renal immune complex deposition. Collectively, our study identified CD4 + T cell-derived exosomal miR‑223‑3p as a cell-origin-associated biomarker in SLE, while also acting as a pathogenic regulator through the FBXW7/mitophagy axis and modulation of T-B cell crosstalk. Its therapeutic efficacy in vivo supports its potential as a candidate for exosome‑based therapy in SLE, but the evidence remains preliminary.
    Keywords:  CD4 + T; Exosome; FBXW7; Mitophagy; Systemic lupus erythematosus; miRNA
    DOI:  https://doi.org/10.1186/s12951-026-04764-w
  70. J Clin Invest. 2026 Jun 30. pii: e197274. [Epub ahead of print]
    Dysregulated methylation‒ubiquitination crosstalk accelerates intervertebral disc degeneration via MED12 destabilization and cGAS/STING activation.
    Huaizhen Liang, Dingchao Zhu, Zhi Du, Xinyu Li, Rui Shi, Jie Lei, Bide Tong, Hanpeng Xu, Di Wu, Xingyu Zhou, Yifan Du, Zixuan Ou, Junyu Wei, Shuchang Peng, Wencan Ke, Zhiwei Liao, Bingjin Wang, Kun Wang, Xiaobo Feng, Yu Song, Cao Yang.
      Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet clinically, there remains no effective therapeutic approach to reverse its progression, imposing a substantial socioeconomic burden. While multiple factors contribute to IVDD pathogenesis, cellular senescence has emerged as a critical risk factor associated with both the incidence and progression of IVDD. Ageing and other damage factors drive nucleus pulposus cells (NPCs) towards a senescent phenotype characterized by increased secretion of proinflammatory factors, resulting in NPC dysfunction and tissue degeneration, which are hallmarks of IVDD. In this study, we demonstrated that PRMT2 deficiency disrupted arginine methylation‒ubiquitination crosstalk, driving NPC inflammatory senescence and accelerating IVDD progression. Mechanistically, PRMT2 loss reduced FBXO7 methylation at Arg 504, promoting the FBXO7-MED12 interaction to facilitate MED12 ubiquitination and subsequent proteasomal degradation. MED12 deficiency induced pathological R-loop accumulation, which activated the cytosolic DNA-sensing cGAS-STING axis, triggering inflammatory response cascades. Notably, engineered extracellular vesicles (EVs) delivering MED12-overexpressing plasmids effectively inhibited NP cell senescence and attenuated IVDD progression. Together, our findings establish that dysregulated methylation‒ubiquitination crosstalk critically drives IVDD progression and reveal MED12 as a promising therapeutic target for ameliorating the impact of IVDD.
    Keywords:  Aging; Bone biology; Cellular senescence; Orthopedics; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI197274
  71. J Am Chem Soc. 2026 Jun 28.
    Silicon-Xanthenium Scaffold for pH- and Far-Red Light Dual-Responsive Photocage.
    Xiaosa Yan, Jia-Hui Zhao, Yaoji Zhu, Weiren Huang, Ling Chu.
      The development of far-red light-activatable photolabile protecting groups (PPGs) is crucial for precision medicine applications, yet remains challenging due to the low energy of far-red light photons and the frequent compromise of aqueous solubility. While conditional PPGs activated by specific biochemical conditions offer enhanced spatial control, their scope is limited by the need for external triggers or heterogeneous enzyme expression. Here, we report a new class of dual-responsive PPGs based on a silicon-xanthenium scaffold that are activated by both acidic pH and far-red light. Through systematic structural modification, we developed pcSiR718-OH, a photocage with a low molecular weight (<500 Da) and a red-shifted absorption maximum at 718 nm. pcSiR718CO2H exhibits efficient uncaging (ε × Φuncagingrel = 184 M-1cm-1) under mildly acidic conditions (pH 5.5-6.7) while remaining stable at physiological pH. Mechanistic studies reveal that photolysis can proceed via both homolytic and heterolytic pathways. We demonstrate the utility of this platform through the precise release of bioactive molecules─pomalidomide and gambogic acid─achieving spatiotemporal control over protein degradation in cellular models and tumor growth inhibition in a murine model. This work establishes a versatile strategy for designing environmentally responsive photocages for targeted therapy.
    DOI:  https://doi.org/10.1021/jacs.6c10574
  72. Int J Nanomedicine. 2026 ;21 607504
    Exosome-Biomaterial Platforms for Diabetic Skin Infections: Microenvironment Remodeling, Responsive Delivery, and Clinical Translation.
    Jian Xiao, Zekun He, Yitian Bu, Yan Lu, Shuibin Liang.
      Diabetic skin infections, particularly diabetic foot ulcers (DFU), remain difficult to treat because infection, biofilm formation, persistent inflammation, oxidative stress, hypoxia, impaired angiogenesis, and extracellular matrix (ECM) disruption coexist within a hostile wound microenvironment. Conventional treatments, including antibiotics, surgical debridement, negative pressure wound therapy, and standard dressings, are indispensable but often fail to simultaneously suppress infection and restore regenerative healing. Exosomes have emerged as promising acellular mediators for diabetic wound repair because they can coordinate immune regulation, angiogenesis, matrix remodeling, and re-epithelialization. However, direct exosome administration is limited by rapid clearance, poor local retention, dilution by wound exudate, dose inconsistency, and manufacturing heterogeneity. Biomaterial platforms, including hydrogels, microneedle patches, membranes, cryogels, porous scaffolds, and responsive nanocomposite systems, provide a rational strategy to protect exosome bioactivity, prolong local retention, and enable sustained or stimulus-responsive release. More importantly, these materials can be engineered to actively regulate infection-associated pathological barriers, including biofilm persistence, excessive oxidative stress, hypoxia, and impaired tissue reconstruction. This review summarizes recent advances in exosome-biomaterial systems for diabetic skin infections, with emphasis on delivery design, microenvironment-responsive release, anti-infective and regenerative mechanisms, platform comparison, and clinical translation. We further discuss key translational challenges, including exosome source selection, dose standardization, potency assays, scalable manufacturing, storage stability, biosafety, regulatory classification, and clinical trial design. Current evidence suggests that exosome-biomaterial systems can improve wound closure, vascularization, collagen deposition, re-epithelialization, and infection control in preclinical models. Nevertheless, high-quality clinical evidence remains limited. Future studies should prioritize clinically relevant infected diabetic wound models, standardized quality-control frameworks, and simplified delivery systems compatible with routine wound care.
    Keywords:  biomaterials; diabetic foot ulcers; diabetic skin infection; exosomes; microenvironment reprogramming; regenerative medicine
    DOI:  https://doi.org/10.2147/IJN.S607504
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