bims-engexo Biomed News
on Engineered exosomes
Issue of 2026–05–24
63 papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Engineering strategies of bacterial outer membrane vesicles for enhancing tumor immunotherapy.
  2. Exosomes in Inflammatory Bowel Disease: Mechanisms, Diagnostic Potential, and Engineering Strategies for Precision Therapy.
  3. Reparative "exosome-ark" for mitochondrial transplantation to reprogram macrophages and disrupt pathogenic crosstalk in pulmonary fibrosis.
  4. The updated role of exosomes in cancer diagnosis and therapy.
  5. Hit the bull's eye: Engineered extracellular vesicles for targeted therapy.
  6. Auto-loaded polydopamine-M2 exosomes as an antioxidative nanoscavenger for lupus erythematosus therapy.
  7. A drug-free, engineered hybrid exosome platform alleviates atherosclerosis via inflammation modulation and phenotype remodeling.
  8. Bioengineered MSC-Derived Extracellular Vesicles in Intervertebral Disc Therapeutics: A Systematic Review.
  9. Precision Engineering of Extracellular Vesicles as Programmable Carriers for mRNA Therapeutics.
  10. Engineered Extracellular Vesicles in Glioma Therapy: Recent Advances and Applications.
  11. Alleviation of diabetic cardiomyopathy via preventing VCAM1-positive cells from senescence by engineered nanovesicles.
  12. Mycobacterium tuberculosis-induced PCBP1 degradation drives macrophage ferroptosis to promote infection: a lung-macrophage-targeted RNAa nanotherapy.
  13. Representative probiotic extracellular vesicles engineered with modified hyaluronic acid and tea polyphenol for enhancing bioactive stability and targeted cellular delivery.
  14. Exosome-modified mesoporous polydopamine with saikosaponin D and ferric ions for immunotherapy of metastatic breast cancer.
  15. The role of targeted exosomes in improving drug delivery in breast cancer: challenges and prospects.
  16. Folate-mediated inflammatory microenvironment-responsive nanocarriers for the delivery of Moringa A to target NLRP3 for the treatment of viral pneumonia.
  17. Mechanistic Study on MSC-EXO Loaded with Salubrinal for the Treatment of Osteomyelitis-Induced Bone Defects.
  18. A fiber-reinforced bioresponsive hierarchical tampon-inspired dressing orchestrates synergistic hemostasis and controlled antioxidant delivery for female reproductive tract repair.
  19. Spleen-tumor dual-targeting vaccines reshape anticancer landscape by activating both innate and adaptive immunity.
  20. Advanced liposomal nanoplatforms for flavonoid delivery: a mechanistic and comparative perspective in hepatocellular carcinoma.
  21. HAMA microneedles patch loaded with Three-Dimensional exosome and Mupirocin promote diabetic wound healing.
  22. The potential of stem cells in breast cancer therapy: A review.
  23. Hypoxia-pretreated exosomes promote enterocutaneous fistula healing via regulating inflammation and tissue repair.
  24. Human mesenchymal stem cell-derived miR-3614-5p exosomes suppress progression of colorectal cancer by targeting IL7Rα.
  25. The Design Strategies and Applications of Engineered Nanoparticles for Traumatic Brain Injury.
  26. Porous Phosphate Glass Microspheres Loaded with Dental Pulp Stem Cell - Derived Exosomes for Potential Osteogenic Applications.
  27. Trends in Pain Relief in Cancer Patients: Pharmacotherapy and Medical Device Therapy.
  28. Plant-Derived Extracellular-Vesicle-Like Particles: Immune Regulation and Disease Therapy.
  29. ALKBH5-Mediated m6A Demethylation Stabilizes HMGB1 to Drive Hepatocyte Pyroptosis and Liver Injury in Heat Stroke: Targeting via Biomimetic Nanodelivery.
  30. Organelle-Targeted Nanotherapeutics for Parkinson's Disease: From Pathogenesis to Preclinical Strategies and Translational Challenges.
  31. Therapeutic Targets, Pharmacological Mechanisms, and Delivery Strategies for Diabetic Peripheral Neuropathy.
  32. Hydrogel delivery platform of engineered apoptotic vesicles for ischemic stroke therapy.
  33. Reconstructing protein conformations to activate follicular enzyme-nutrient reservoirs for reversing follicle aging.
  34. Exosome-Coated Boron-Containing Evodiamine Derivative Triggered by Pathology-Specific Reactive Oxygen Species Targets Myofibroblasts to Ameliorate Hypertrophic Scarring.
  35. Multispecific nanobody degraders co-deplete membrane receptors and enable targeted delivery of diverse payloads.
  36. Differential Modulation of Colonic Inflammaging by Limonin Loaded in Pectin Emulsion Gels with Engineered Fine Structures.
  37. Metabolic Engineering Strategies for Flavonoid Biosynthesis in Saccharomyces cerevisiae: Current Advances and Future Perspectives.
  38. Immunomodulatory Nanocarriers in Multiple Sclerosis: Dual Targeting of Microglia and Mitochondria for Precision Neurotherapy.
  39. Engineering precision oncology: Targeting tumors and immune cells with lentiviral vectors.
  40. Combination Therapy of Sini Decoction and Cyclophosphamide Inhibits Tumor Growth in an Orthotopic Lung Cancer Model.
  41. Dual-Gene CRISPR Editing via Peptide Dendrimers Regulates Redox Balance for Diabetic Wound Repair.
  42. Beyond antibiotics: innovative and translational strategies to overcome antimicrobial resistance.
  43. Porous GelMA microneedle with delivery of AIE molecules via HSF-derived exosomes for hypertrophic scar treatment.
  44. Advancing Parkinson's Prevention: Brain-Specific Lipopolyplex Delivery of the GDNF as a Neuroprotective Gene Therapy.
  45. Targeting skin barrier repair: mechanisms of action, therapeutic evidence, and clinical translation challenges of mesenchymal stem cell-derived exosomes.
  46. Topical Application of Human Umbilical Cord-Derived Mesenchymal Stem Cell Exosomes for a Deep Second-Degree Scald Burn Wound: A Case Report.
  47. Engineered 3D-Lattice Microneedle Array Patches for Enhanced Nanovaccine Delivery to Dendritic Cells in Cancer Immunotherapy.
  48. Inducible secretion of LIGHT by engineered probiotics enables localized cytokine therapy and robust antitumor immunity.
  49. Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering.
  50. Mechanistic reprogramming by stem cell-derived extracellular vesicles: From cargo sorting to tissue regeneration.
  51. Hypoxia-Mediated Downregulation of Exosomal miR-128-3p Promotes Lymphangiogenesis via VEGF-C in Oral Squamous Cell Carcinoma.
  52. Functional shell engineering of bioactive wheat-seedling nanovesicles with chitosan derivatives for synergistic metabolic therapy via enhanced oral delivery.
  53. Hydroxychloroquine Inhibits Porcine Epidemic Diarrhea Virus Infection by Targeting Post-Attachment Stages and Virus-Induced Inflammation In Vitro.
  54. Injectable polysaccharide-based hydrogel delivering Poria cocos extracellular vesicles promotes hair regeneration in androgenetic alopecia via Wnt/β-catenin signaling.
  55. Nanoparticle-Based delivery of proteasome inhibitors for glioblastoma Therapy: Strategies to overcome Blood-Brain barrier and therapeutic resistance.
  56. Tolerogenic Nanovaccine Synergizing Citrullinated Peptide and TSP-1 Plasmid for Antigen-Specific Immunotherapy of Rheumatoid Arthritis.
  57. Gastric Cancer-Derived Exosomal MATN3 Favours Immunosuppressive Tumour Microenvironment by Activating Autophagy in an EGFR/ELK1/ATG12 Signalling Dependent Manner.
  58. Targeted delivery of the BCG vaccine to dendritic cells improves protective efficacy against Mycobacterium tuberculosis.
  59. Human umbilical cord mesenchymal stromal cells-derived exosomes from MSCs pretreated with inflammatory factors attenuate renal injury of diabetic mice by regulating macrophage polarization.
  60. Rational engineering of ribitol dehydrogenase for enhanced thermostability and efficient biocatalytic production of allitol.
  61. Assessment of Diagnostic Efficacy of Engineered ESAT-6 Linear Epitopes Based on IFN-γ Secretion in Tuberculosis.
  62. Combining receptor engineering and intracellular gelation for cell-based antiviral therapy against coxsackievirus B3.
  63. Exosome-functionalized alginate/gelatin composite scaffolds: synergistic enhancement of osteogenic differentiation for bone tissue engineering.
  1. Nanoscale. 2026 May 22.
    Engineering strategies of bacterial outer membrane vesicles for enhancing tumor immunotherapy.
    Zhengxin Yu, Yichuan Ma, Qi Guo, Huifang Liu, Zhenhua Li, Jinchao Zhang.
      Outer membrane vesicles (OMVs) have emerged as highly promising bio-derived nanoplatforms in tumor immunotherapy due to their inherent immunogenicity, structural diversity, and molecular customization capabilities. Recent studies have introduced various engineering strategies to enhance their therapeutic efficacy, yet these approaches are often presented as isolated modifications lacking a unified functional theoretical framework. This paper categorizes OMVs engineering techniques into pre-isolation and post-isolation strategies, analyzing how they regulate antigen presentation, immune activation, biodistribution, and therapeutic integration within the tumor immune cycle. By comparing the advantages, limitations, and applicable scenarios of genetic, metabolic, chemical, and physical modifications, we propose a function-oriented design framework. Simultaneously, we address critical challenges including safety control, production consistency, and mechanism standardization, charting future pathways for translating engineered OMVs into clinically viable cancer immunotherapies.
    DOI:  https://doi.org/10.1039/d6nr01038e
  2. Int J Med Sci. 2026 ;23(6): 2141-2153
    Exosomes in Inflammatory Bowel Disease: Mechanisms, Diagnostic Potential, and Engineering Strategies for Precision Therapy.
    Zhong-Kuo Zhao, Jia-le Ma, Fei Lu, Shou-Jie Wang.
      Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder characterized by immune dysregulation, epithelial barrier dysfunction, and microbial imbalance. Despite progress in biologic therapies, challenges such as variable efficacy, systemic side effects, and the lack of reliable biomarkers remain significant obstacles in clinical management. Exosomes, key mediators of intercellular communication, play a pivotal role in IBD's pathogenesis by transporting bioactive substances. Increasing evidence links exosomes to critical IBD processes, including Th17/Treg imbalance, inflammasome activation, and host-microbiome interactions. Exosomes also show potential as minimally invasive biomarkers for disease activity and subtype differentiation. Furthermore, advancements in exosome engineering, including surface modification and hybrid nanostructure development, enhance their potential for targeted drug delivery and immune modulation in IBD. This review summarizes the role of exosomes in IBD, their diagnostic potential, and emerging exosome-based therapeutic strategies.
    Keywords:  engineered exosomes; immune modulation; inflammatory bowel disease; precision therapy
    DOI:  https://doi.org/10.7150/ijms.131676
  3. Mater Today Bio. 2026 Jun;38 103201
    Reparative "exosome-ark" for mitochondrial transplantation to reprogram macrophages and disrupt pathogenic crosstalk in pulmonary fibrosis.
    Xin-Yue Zhang, Yi-Na Liu, Bo Wang, Chen-Guang Zhang, He-Qi Cheng, Xing-Rong Yang, Jin-Huan Wan, Xue-Cheng Sheng, Bin Guo, Hu-Lin Jiang, Xin Chang.
      Pulmonary fibrosis (PF) progresses through a vicious cycle of crosstalk between injured alveolar epithelial cells II (AECs II) and alveolar macrophages. While mitochondrial transplantation offers a promising cure for macrophage metabolic dysfunction, the efficacy is hampered by poor targeting and rapid loss of mitochondrial integrity in vivo. Herein, we engineered a hierarchical strategy that integrates biomanufacturing, organelle protection and metabolic reprogramming. Initially, we utilized a "hijacking" strategy for manufacturing, where lipid nanoparticles (LNPs) delivering a mitochondrial-targeting sirtuin 3 plasmid (pMTS-SIRT3) rejuvenated injured AECs II, transforming them into factories for reparative exosomes. These harvested vesicles were then engineered into an "Exosome-Ark" by encapsulating healthy mitochondria. The pro-reparative intra-exosomal microenvironment functions as a cytoplasm-like milieu to maintain the biological activity of the isolated mitochondria, while mannose functionalization ensured macrophage-specific targeting. In bleomycin (BLM)-induced PF mice model, "exosomes-ark" restored macrophage mitochondrial homeostasis through enhanced fusion-fission dynamics and metabolic reprogramming, suppressed transforming growth factor-β (TGF-β) expression, and attenuated myofibroblast activation. Mechanistically, exosomal reparative signals promoted macrophages for mitochondrial engraftment, revealing a synergistic effect beyond simple organelle replacement. This study presented a biologically inspired platform, offering a translational potential for treating fibrotic diseases driven by AECs II-immune cell crosstalk.
    Keywords:  Engineered exosomes; Exosome-ark; Macrophage reprogramming; Pathogenic crosstalk; Pulmonary fibrosis; Safe mitochondria transplantation
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103201
  4. Discov Oncol. 2026 May 18.
    The updated role of exosomes in cancer diagnosis and therapy.
    Xinlong Huang, Yafei Huang, Xiangcong Wei, Ya Xu.
      Exosomes are nanoscale extracellular vesicles secreted by cells via endosomal pathways. They mediate intercellular communication by transporting bioactive molecules, including proteins, lipids, and nucleic acids. During tumorigenesis, exosomes critically participate in multiple oncogenic processes, including metastatic dissemination, immune evasion, tumor microenvironment remodeling, angiogenesis, and the development of chemoresistance. Comprehensive characterization and molecular profiling of vesicular surface epitopes are essential for tracing their origins. These membrane-bound biomarkers not only facilitate precise vesicle classification but also enable the selective enrichment of tissue-specific molecular signatures that are crucial for targeted therapeutic applications. Accumulating evidence indicates that tumor-derived exosomes have emerged as promising diagnostic biomarkers with exceptional specificity, while their intrinsic biocompatibility and cargo-loading capacity confer transformative potential for next-generation drug delivery platforms. This review critically examines exosome roles in tumor biology. It highlights clinical applications in oncology. We focus on exosome biomarkers in liquid biopsy, engineered exosomes for drug delivery, and pharmacological or genetic strategies targeting exosome biogenesis.
    Keywords:  Diagnosis; Drug delivery; Exosomes; Therapy; Tumor
    DOI:  https://doi.org/10.1007/s12672-026-05193-9
  5. Bioact Mater. 2026 Oct;64 324-358
    Hit the bull's eye: Engineered extracellular vesicles for targeted therapy.
    Yijin Cai, Hengjing Zhang, Xinao Fan, Haojie Fu, Haiyan Li, Xiaoling Fu, Xudong Wang, Changyong Yuan, Kaili Lin, Yu Zhuang.
      Extracellular vesicles (EVs) are nanoscale vesicles secreted by most cell types and have a similar composition to their parent cells. By delivering effector molecules, EVs serve as mediators of intercellular communication and hold significant therapeutic potential. However, challenges such as uncertain in vivo biodistribution and the risk of adverse reactions in non-target tissues still limit their broader clinical translation. Recent studies increasingly demonstrate that EVs can be engineered to target pathological tissues, thereby enhancing their specificity and therapeutic efficacy across various diseases. This review first outlines the biogenesis, composition, trafficking, cellular uptake, and biological functions of EVs, followed by a description of their natural biodistribution patterns, emphasizing how molecular heterogeneity contributes to natural targeting. We then discuss engineering strategies for EV targeting, comparing their advantages, limitations, and industrial feasibility. Subsequently, we examine how organ-specific microenvironment influences targeting efficiency of engineered EVs and summarize their applications in targeted therapy across various organs and tissues. Finally, the major challenges and future directions for the clinical translation of engineered EVs in targeted therapy are highlighted.
    Keywords:  Clinical translation; Engineering strategies; Extracellular vesicles; Targeted therapy
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.04.035
  6. Mater Today Bio. 2026 Jun;38 103199
    Auto-loaded polydopamine-M2 exosomes as an antioxidative nanoscavenger for lupus erythematosus therapy.
    Huiyuan Ye, Shufan Hou, Xingyu Li, Yujuan Zhu, Zhifeng Gu, Mei Yang.
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation and immune dysregulation, predominantly affecting women of reproductive age. Current treatments, including antimalarials, corticosteroids, and immunosuppressants, often entail long-term toxicity. To address this, we developed an auto-loaded polydopamine-M2 exosome system (M2/pEXO) as an antioxidative nanoscavenger for SLE therapy. Ultrasmall PDA nanoparticles facilitated M2 macrophage polarization and were autonomously encapsulated into exosomes during polarization, yielding M2/pEXO with enriched protein content and enhanced cellular uptake. Proteomic analysis indicated that M2/pEXO cargo proteins are involved in cellular energy metabolism and inflammatory regulation, underpinning its immunomodulatory and antioxidant functions. Compared with conventional M2 EXO, M2/pEXO exhibited superior antioxidative and anti-inflammatory effects, reducing M1 macrophage polarization and pro-inflammatory cytokine secretion while promoting regulatory T cell expansion. In a murine SLE model, M2/pEXO significantly alleviated lupus nephritis, attenuating renal immune infiltration, glomerular mesangial proliferation, proteinuria, serum creatinine, and anti-dsDNA autoantibody levels, without detectable toxicity. The platform elevates M2 EXO from mere anti-inflammatory carriers to an integrated nanoscavenger system capable of targeted delivery, oxidative stress scavenging, and immunomodulation. This auto-loaded, naturally engineered strategy presents a safe and effective therapeutic approach for SLE and potentially other chronic inflammatory diseases.
    Keywords:  Antioxidative nanoscavenger; Auto-loaded polydopamine; Lupus erythematosus; M2 exosome; Systemic immunotherapy
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103199
  7. Colloids Surf B Biointerfaces. 2026 May 19. pii: S0927-7765(26)00421-2. [Epub ahead of print]266 115833
    A drug-free, engineered hybrid exosome platform alleviates atherosclerosis via inflammation modulation and phenotype remodeling.
    Xi Yang, Fenting Lei, Xinghui He, Mengxi Wu, Yilin Liu, Qi Li, Xiao Tan, Keyi Ding, Ting Zhao, Ziyi Liu, Xin Yu, Hong Yu, Chunhong Li.
      Elevated concentrations of reactive oxygen species (ROS) within the atherosclerotic microenvironment initiate positive feedback loops involving inflammatory mediators, consequently triggering an inflammatory storm between endothelial cells and macrophages. Currently, the treatment of atherosclerosis (AS) mainly focuses on removing lipids, without effective anti-inflammatory and antioxidant therapies. AgNPs with anti-inflammatory and ROS-scavenging functions demonstrate promising therapeutic effects against inflammation. Here, given the acidic microenvironment and inflammatory characteristics of the disease, we proposed a drug-free, engineered hybrid exosome platform (Lipo/exo-AgNPs) by fusing pH-sensitive liposomes with M2-type macrophage-derived exosomes (M2-exo) to encapsulate silver nanoparticles (AgNPs). Leveraging the messenger functions and inflammatory homing properties of M2-exo, Lipo/exo-AgNPs can maintain stable circulation in the blood and specifically target damaged endothelial cells and inflammatory macrophages within plaques. In vitro studies demonstrated that Lipo/exo-AgNPs exhibited enhanced uptake efficiency in both damaged endothelial cells and inflammatory macrophages. In ApoE-/- mouse model, treatment with the preparation significantly attenuated atherosclerotic plaque deposition and suppressed inflammatory responses. In conclusion, Lipo/exo-AgNPs effectively addressed the insufficient targeting specificity of traditional exosome delivery systems. Moreover, Lipo/exo-AgNPs not only enabled intelligent, controlled, and responsive drug delivery, but also elevated atherosclerosis treatment from a simple lipid-lowering strategy to a new level of microenvironment remodeling through a "triple synergistic enhancement" mechanism involving inflammation targeting-endothelial repair-phenotype reprogramming.
    Keywords:  Atherosclerosis; Drug-free; Engineered hybrid exosome platform; Inflammation modulation; Phenotype remodeling
    DOI:  https://doi.org/10.1016/j.colsurfb.2026.115833
  8. Acta Biomater. 2026 May 21. pii: S1742-7061(26)00324-7. [Epub ahead of print]
    Bioengineered MSC-Derived Extracellular Vesicles in Intervertebral Disc Therapeutics: A Systematic Review.
    Ana Margarida Vieira Martins, Sofia Pilão, Susana Gomes Santos, Cornelia Neidlinger-Wilke, Anita Ignatius, Raquel Madeira Gonçalves, Graciosa Quelhas Teixeira.
      Intervertebral disc degeneration (IVDD) is a major contributor to chronic low back pain, representing a significant global health burden. Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic strategy, with preclinical evidence demonstrating their ability to modulate inflammation, oxidative stress, apoptosis, senescence, and extracellular matrix (ECM) degradation. However, several challenges limit translation, including inconsistent EV isolation methods, incomplete mechanistic characterization, lack of standardized dosing, and limited long-term or large-animal validation. Bioengineering of EVs can contribute to overcome some of these limitations, namely improving EV bioactivity, controlling cargo composition, and enabling targeted delivery. This systematic review synthetizes bioengineering strategies aimed at improving the efficacy of MSC-EVs in the avascular disc environment. In vitro, ex vivo, and in vivo studies investigating primed or engineered MSC-EVs for IVDD were systematically analyzed. MSC-EVs consistently attenuated pro-inflammatory signaling, reduced oxidative stress, limited apoptosis, pyroptosis, and ferroptosis, and restored ECM homeostasis. Mechanistic pathways activated by engineered EVs were extracted and critically synthesized. Engineering strategies, including cargo loading, surface modification, and donor-cell priming, enhanced EV potency, specificity, and yield. Biomaterial-assisted delivery systems, such as injectable hydrogels, microspheres, and decellularized matrix scaffolds, improved EV retention, protection, and sustained release within the IVD, markedly enhancing therapeutic outcomes compared to direct injection. Overall, MSC-EVs represent a robust, multimodal therapeutic platform capable of targeting the core degenerative mechanisms of IVDD. When combined with bioengineering strategies and advanced biomaterial carriers, MSC-EVs offer a promising next-generation, minimally invasive approach with strong potential for clinical translation in IVDD. STATEMENT OF SIGNIFICANCE: Intervertebral disc degeneration (IVDD) remains a major cause of disability, and current therapies fail to restore disc structure or function. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising cell-free therapeutic approach; however, their mechanism-of-action, engineering potential, and biomaterial-based delivery strategies have not been comprehensively evaluated. This systematic review is the first to integrate evidence on native, primed, and engineered MSC-EVs while critically analyzing biomaterial-assisted delivery systems that enhance EV retention, protection, and controlled release within the avascular disc. By synthesizing mechanistic pathways, evaluating engineering strategies, and identifying key translational challenges in isolation and dosing, this work provides a framework for developing next-generation EV-biomaterial hybrid therapeutics targeting the underlying biology of IVDD.
    Keywords:  biomaterials; cargo engineering; extracellular vesicles; hydrogels; intervertebral disc degeneration; mesenchymal stromal cells; priming; regenerative medicine
    DOI:  https://doi.org/10.1016/j.actbio.2026.05.036
  9. Int J Nanomedicine. 2026 ;21 595161
    Precision Engineering of Extracellular Vesicles as Programmable Carriers for mRNA Therapeutics.
    Hyejoo Yoon, Gyuwon Lee, Junyeong Jo, Jain Koo, Eun-Hee Kim, Hyun Jin Choi, Sangyong Jung, Yuseon Shin, Kyung Taek Oh, Chaemin Lim.
      Messenger RNA (mRNA) therapeutics have rapidly evolved into a transformative modality for treating infectious diseases, cancer, and genetic disorders; however, the clinical translation of these therapeutics remains limited by the need for safe, efficient, and tissue-specific delivery vehicles. Subsequently, extracellular vesicles (EVs) have emerged as a promising next-generation platform due to the associated endogenous biogenesis, intrinsic biocompatibility, low immunogenicity, and natural ability to traverse biological barriers. Thus, this review provides a comprehensive evaluation of the major engineering strategies enabling EV-based mRNA delivery, including exogenous loading methods, endogenous genetic engineering, physical microenvironment-driven enhancement, and hybrid EV-synthetic nanoparticle systems. Moreover, this review summarizes advances in electroporation, lipid-mediated fusion, and chemical/physical loading techniques; programmable endogenous loading platforms leveraging EV-sorting proteins and RNA-binding domains; cargo release mechanisms employing self-cleaving, protease-sensitivity, and optogenetic modules; device- and substrate-based approaches that modulate EV biogenesis and cargo composition. We further highlight emerging hybrid EV systems-particularly fusogenic cubosome-EV constructs-that achieve near-quantitative mRNA encapsulation and improved biodistribution, including enhanced penetration across the blood-brain barrier. Finally, we discuss technological bottlenecks and translational considerations, including scalability, batch variability, long-term mRNA stability, and regulatory challenges associated with biologically derived carriers. Collectively, this review outlines the current landscape and future directions for precision engineering of EVs as programmable, clinically viable carriers for mRNA therapeutics.
    Keywords:  drug loading; engineering EV; extracellular vesicles; hybrid EVs; mRNA delivery
    DOI:  https://doi.org/10.2147/IJN.S595161
  10. Int J Nanomedicine. 2026 ;21 609673
    Engineered Extracellular Vesicles in Glioma Therapy: Recent Advances and Applications.
    Linjin Xiong, Xintian Yu, Tao Chen, Wei Gao, Kexin Wang, Yijin Fu, Yourong Yin, Xue Zhou, Yuhang Xia, Xinli Cui, Linan Zeng, Lingli Zhang, Yantao Liu.
      Gliomas are a highly heterogeneous group of primary tumors of the central nervous system. The blood-brain barrier and the complex tumor microenvironment restrict drug penetration and reduce the effectiveness of standard chemotherapy. Extracellular vesicles (EVs) have gained attention as potential delivery vehicles because they can move across biological barriers, are generally well tolerated, and naturally shuttle signals between cells. However, unmodified EVs face practical hurdles for clinical use, including limited tissue targeting, modest drug payload capacity, low manufacturing yield, and imperfect control over what they carry. To overcome these constraints, growing efforts have focused on engineering EVs to improve delivery performance and therapeutic precision. This review outlines key EV characteristics and commonly used isolation methods, with an emphasis on engineering approaches for glioma therapy. We also summarize recent progress in engineered EV-based treatments for glioma and discuss the main barriers to clinical translation.
    Keywords:  engineering; extracellular vesicles; glioma; glioma therapy; multimodal therapy
    DOI:  https://doi.org/10.2147/IJN.S609673
  11. J Nanobiotechnology. 2026 May 17.
    Alleviation of diabetic cardiomyopathy via preventing VCAM1-positive cells from senescence by engineered nanovesicles.
    Yang Liu, Shuang Liang, Fan Bu, Pengying Wu, Xueying Zhou, Jing Zhao, Mingzhi Shen, Mengying Wei, Guodong Yang, Lijun Yuan.
      Diabetic cardiomyopathy (DCM) involves progressive cardiac dysfunction driven by vascular endothelial injury and cellular senescence. However, precisely targeting pre-senescent cells remains a major therapeutic challenge. Herein, through single-cell RNA sequencing of diabetic mouse hearts, we identified VCAM1 -positive (VCAM1+) cells as a distinct pre-senescent endothelial population. Both scRNA-seq and subsequent immunofluorescence analyses confirmed the concurrent upregulation of cGAS-STING signaling within this VCAM1 + population, nominating it as a critical therapeutic target for early intervention. To specifically deliver a STING antagonist to these cells, we developed a biomimetic delivery platform based on engineered HEK293T cell-derived nanovesicles. Through lipidomic analysis, we reprogrammed the vesicle membrane composition to mimic that of endothelial cells, thereby creating nanovesicles with enhanced membrane fusogenic properties (F-NVs). After loading with H151, a potent STING pathway inhibitor that acts by inhibiting STING phosphorylation, the resulting F-NVs-tVCAM1@H151 efficiently targeted VCAM1 + pre-senescent cells, potently inhibited their transition into a senescent state, and significantly reduced the overall senescent burden in the diabetic heart. Consequently, this targeted strategy alleviated cardiac microvascular injury and markedly improved cardiac function in diabetic mice. This work identifies VCAM1 as a novel pre-senescent marker and demonstrates membrane lipid engineering as an effective approach for targeted nanovesicle delivery, offering a precise targeted therapeutic paradigm for DCM.
    Keywords:  Diabetic cardiomyopathy; Endothelial senescence; Membrane lipid engineering; Nanovesicles; Targeted drug delivery; cGAS-STING pathway
    DOI:  https://doi.org/10.1186/s12951-026-04555-3
  12. J Nanobiotechnology. 2026 May 21.
    Mycobacterium tuberculosis-induced PCBP1 degradation drives macrophage ferroptosis to promote infection: a lung-macrophage-targeted RNAa nanotherapy.
    Huan-Shao Huang, Jia-Xin Chi, Jia-Jun Wang, Le-Yao Xiao, Lan Chen, Shi-Ying Lai, Wan-Yi Liu, Feng Yang, Kang-Sheng Liao, Jiang Pi, Yan-Guang Cong, Yi-Ming Shao, Jun-Fa Xu.
       BACKGROUND: Immune evasion by Mycobacterium tuberculosis (Mtb) complicates tuberculosis (TB) therapy. Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a critical process in host-pathogen interactions. We aimed to define the role of poly(C)-binding protein 1 (PCBP1) in macrophage ferroptosis during Mtb infection and to develop a targeted RNA activation (RNAa) nanotherapy to exploit this pathway.
    METHODS: We analyzed clinical samples from TB patients and investigated Mtb-host interactions in macrophage models using molecular and biochemical assays. Mannosylated lipid nanoparticles (MLNPs) were engineered to deliver PCBP1-targeting small activating RNAs (saRNAs). Therapeutic efficacy, lung-specific delivery, and biocompatibility were evaluated in a murine TB model.
    RESULTS: Mtb utilizes the host E3 ubiquitin ligase Trim21 to mediate the proteasomal degradation of PCBP1. PCBP1 loss induced macrophage ferroptosis by modulating its downstream targets GPX4, PTGS2, and HMOX1, promoting bacterial survival. In vitro, saPCBP1@MLNPs restored PCBP1 expression, reversed ferroptosis markers (Fe²⁺, 4-HNE), and reduced Mtb burden. In murine models, the nanotherapy achieved lung-specific delivery, significantly attenuated lung pathology, and enhanced bacterial clearance.
    CONCLUSIONS: PCBP1 is a critical, druggable immune-metabolic checkpoint that governs macrophage ferroptosis in TB. Our targeted RNAa nanotherapy represents a promising host-directed strategy for Mtb infection, linking a key molecular mechanism to a translational therapeutic platform and offering a new approach for treating drug-resistant TB.
    Keywords:   Mycobacterium tuberculosis ; Ferroptosis; Host-directed therapy; Nanotherapy; PCBP1; RNA activation (RNAa)
    DOI:  https://doi.org/10.1186/s12951-026-04569-x
  13. Food Res Int. 2026 Aug 01. pii: S0963-9969(26)01047-1. [Epub ahead of print]237 119370
    Representative probiotic extracellular vesicles engineered with modified hyaluronic acid and tea polyphenol for enhancing bioactive stability and targeted cellular delivery.
    Taisong Fang, Songbai Liu.
      Curcumin (Cur) and anthocyanin (Ant) are typical plant-derived bioactives with promising biological benefits, but poor stability and bioavailability limit their applications. To address these challenges, we engineered a targeted co-delivery platform by systematically comparing two representative, probiotic-derived extracellular vesicle carriers: outer membrane vesicles (OMVs) from Escherichia coli Nissle 1917 and extracellular vesicles (EVs) from Lactobacillus plantarum. Encapsulation efficiency (EE) of Cur was 41.6% for OMVs and 35.9% for EVs, whereas EE of Ant was 25.4% and 24.6%, respectively. Both vesicle types were further synergistically functionalized with specifically acylated epigallocatechin palmitate (EGCp) and octenyl succinic anhydride-grafted hyaluronic acid (OSA-HA). The incorporation efficiency of EGCp was 27.2% for OMVs and 37.3% for EVs. The self-assembly process yielded composite nanovesicles with a reduced particle size (OMVs: from 165.6 nm to 143.2 nm; EVs: from 156.8 nm to 120.8 nm) and a more negatively charged surface (from -20.8 mV to -37.5 mV for OMVs; from -18.3 mV to -35.3 mV for EVs) compared to their native counterparts, indicating improved colloidal properties. In addition, both engineered nanovesicles effectively protected the encapsulated bioactives, significantly enhancing their stability against simulated gastrointestinal digestion and oxidative stress. For example, the retention of Cur under oxidative conditions increased from 24.2% in unmodified OMVs to 69.1% in the optimized formulation within 2 h. Cellular uptake assays confirmed the OSA-HA coating achieved targeted delivery to inflammatory macrophages, with OSA-HA-modified OMVs exhibiting higher cellular internalization (75.4% at 12 h) than similarly modified EVs (61.8% at 12 h). While both types of functionalized nanovesicles enhanced intracellular antioxidant activity to a similar extent, the OMV-based system demonstrated superior suppression of pro-inflammatory mediators (NO, TNF-α, and IL-6) in mitigating lipopolysaccharide (LPS)-induced cell damage. This comparative study establishes a biocompatible probiotic-based colloidal platform, demonstrating the potential of two selected engineered probiotic vesicles and functionalized polysaccharides for the encapsulation and targeted cellular delivery of sensitive bioactive compounds.
    Keywords:  Anti-inflammatory; Bioactive compounds; Functionalized polysaccharides; Probiotic extracellular vesicles; Targeted delivery; Tea polyphenols
    DOI:  https://doi.org/10.1016/j.foodres.2026.119370
  14. J Mater Chem B. 2026 May 20.
    Exosome-modified mesoporous polydopamine with saikosaponin D and ferric ions for immunotherapy of metastatic breast cancer.
    Mengzhu Zhang, Yuzhu Hou, Botong Liu, Fei Yan, Rui Su.
      Metastatic breast cancer remains a critical clinical challenge with limited therapeutic options, severe tumor metastasis and unsatisfactory single-treatment efficacy, and it is urgent to develop targeted and synergistic therapeutic strategies to improve anti-tumor outcomes. In this study, we developed a novel tumor-targeted nanomedicine (MFSE) based on exosome-modified mesoporous polydopamine (MPDA) loaded with saikosaponin D (SSd) and ferric ions (Fe3+) to achieve synergistic photothermal and drug therapies for improved anti-tumor efficacy. The internal pore size of MPDA matched the structural characteristics of SSd molecules, facilitating efficient loading and controlled release of SSd and preventing drug degradation. Importantly, Fe3+ doping enhanced the photothermal conversion efficiency by 38.68% compared with that of undoped MPDA. Owing to the homing effect of exosomes, MFSE exhibited superior cellular internalization and tumor accumulation. Upon 808 nm laser irradiation, the released SSd combined with the photothermal effect of MPDA to exert a synergistic anti-tumor effect, which effectively eliminated tumor cells, elicited immune responses, and significantly suppressed primary tumors, distant tumors, and lung metastases. Meanwhile, the MFSE-based therapeutic strategy displayed no obvious adverse effects and excellent biocompatibility in vivo. Overall, this study established a reliable and effective paradigm for the rational design of exosome-integrated nanoplatforms for precise targeting and synergistic therapy against metastatic breast cancer.
    DOI:  https://doi.org/10.1039/d6tb00717a
  15. Mol Biol Rep. 2026 May 21. pii: 791. [Epub ahead of print]53(1):
    The role of targeted exosomes in improving drug delivery in breast cancer: challenges and prospects.
    Mehrad Zibaei Moghadam, Mahdiyeh Shafieesabet, Nazanin Jamshidi, Negar Jamshidi.
      Breast cancer is one of the most common and deadly types of cancer in women, and its treatment is associated with several challenges, including drug resistance, drug side effects, and inadequate targeting of cancer cells. In recent years, the use of exosomes as natural drug carriers has attracted much attention due to their properties such as high biocompatibility, ability to cross biological barriers, and ability to target specific cells. Targeted exosomes, by surface modification and loading of chemotherapeutic drugs, regulatory RNAs, and other therapeutic molecules, enable more effective drug delivery and reduce systemic toxicity. This review article will examine the role of targeted exosomes in improving drug delivery in breast cancer in a narrative manner. First, the structure and biological properties of exosomes and different drug loading methods are described. Then, the preclinical and clinical applications of exosomes in the delivery of various drugs and their effects on cancer cells and cancer stem cells are reviewed. The main challenges in the use of exosomes are also discussed, including standardization of isolation and detection methods, precise control of drug loading, unfavorable stability and biodistribution, and issues related to mass production and safety. Finally, the future prospects of this field are discussed, focusing on novel exosome engineering technologies, combination with immunotherapies, and development of more precise targeting methods. This review shows that targeted exosomes have great potential to improve the efficacy of breast cancer therapies, but further research and resolution of technical and clinical challenges are required for widespread clinical entry.
    Keywords:  Bioengineering of exosomes; Breast cancer; Drug delivery; Drug resistance; Nanodrug delivery; Targeted exosomes
    DOI:  https://doi.org/10.1007/s11033-026-11635-y
  16. Int J Pharm X. 2026 Jun;11 100565
    Folate-mediated inflammatory microenvironment-responsive nanocarriers for the delivery of Moringa A to target NLRP3 for the treatment of viral pneumonia.
    Taoyuan Zeng, Jiayu Li, Wenyi Yao, Xu Cheng, Dandan Yang, Chunmei Lv, Yongai Xiong.
      Cytokine storm triggered by respiratory viral infection is the core pathogenic mechanism of severe pneumonia, and excessive activation of the NLRP3 inflammasome is a critical link in inducing this storm and subsequent lung tissue damage. This study targets the NLRP3 inflammasome to investigate the therapeutic effects, mechanisms of action, and targeted delivery advantages of folic acid-modified nanoparticles encapsulating Moringa A (MA NPs) for viral pneumonia. Utilizing techniques such as cellular experiments, mouse model validation, molecular docking, bio-layer interferometry (BLI), immunohistochemistry, immunofluorescence, and histopathology, this study systematically analyzed the effects of MA NPs on the NLRP3 inflammasome pathway, pyroptosis, macrophage polarization, and lung tissue injury, while also validating the targeting efficacy of the folic acid-modified nanodelivery system. The results showed that MA NPs significantly reduced the expression of NLRP3, ASC, Caspase-1, and GSDMD in H1N1 virus-infected cells, decreased the levels of pyroptosis-related cytokines, and MA was confirmed to be an NLRP3 inhibitor. In mouse models, MA NPs reduced the lung index, downregulated the expression of pro-inflammatory cytokines in lung tissue, and alleviated pathological and ultrastructural damage to lung tissue. Furthermore, MA NPs inhibited the excessive activation of the NLRP3 inflammasome and promoted the polarization of macrophages from the M1 phenotype to the M2 phenotype, thereby alleviating the pulmonary inflammatory microenvironment. Therefore, MA NPs can repair lung tissue damage by inhibiting excessive activation of the NLRP3 inflammasome and regulating macrophage polarization, and combined with the folic acid-targeted delivery system, achieve precision treatment for viral pneumonia. This provides a new approach and experimental basis for the synergistic intervention of viral pneumonia.
    Keywords:  Moringa A; NLRP3; Pyroptosis; Viral Pneumonia
    DOI:  https://doi.org/10.1016/j.ijpx.2026.100565
  17. FASEB J. 2026 May 31. 40(10): e71703
    Mechanistic Study on MSC-EXO Loaded with Salubrinal for the Treatment of Osteomyelitis-Induced Bone Defects.
    Xi Yue, Xiaomeng Song, Jinliang Wu, Zihe Liu, Yan Wang, Guanhao Chen, Wenshuya Li, Hongyu Tan, Kerong Yang.
      Osteomyelitis-related bone defects arise from bacterial infection-induced tissue damage and inadequate repair, resulting in pain, swelling, and functional loss. Here, we evaluated locally delivered salubrinal-loaded mesenchymal stem cell-derived exosomes (Sal-MSC-exo) in a rat model of infectious osteomyelitis. After characterizing MSCs, their exosomes, and drug-loading efficiency, we established a Staphylococcus aureus-induced osteomyelitis model and assigned rats to five groups: control, infected, salubrinal (Sal), exosome (Exo), and Sal-MSC-exo. Outcomes included histology and micro-CT, osteoblast proliferation (EdU), ER ultrastructure (electron microscopy), immunohistochemistry, Western blotting, and cell migration assays (transwell and scratch). These analyses assessed osteoblast proliferation and apoptosis, ER-stress signaling, extracellular matrix proteins, autophagy-related markers, and inflammatory activation. Sal-MSC-exo partially restored trabecular architecture, suppressed osteoblast apoptosis, and enhanced osteoblast migration compared with infected controls and single-agent groups. Mechanistically, Sal-MSC-exo attenuated ER stress, evidenced by upregulation of p-eIF2α and ATF4 with concomitant reduction of CHOP. In parallel, Sal-MSC-exo modulated autophagy-associated with increased p-eIF2α, eIF2α, LC3-I/II, and ALP and reduced p62-consistent with relief of maladaptive ER-stress-autophagy cross talk. Collectively, these findings indicate that Sal-MSC-exo mitigates osteomyelitis-associated bone loss and supports bone repair, highlighting its translational potential as a localized therapy for infection-induced bone defects.
    Keywords:  bone regeneration; endoplasmic reticulum stress; mesenchymal stem cell–derived exosomes; osteomyelitis; salubrinal
    DOI:  https://doi.org/10.1096/fj.202502940R
  18. Int J Biol Macromol. 2026 May 21. pii: S0141-8130(26)02519-5. [Epub ahead of print] 152592
    A fiber-reinforced bioresponsive hierarchical tampon-inspired dressing orchestrates synergistic hemostasis and controlled antioxidant delivery for female reproductive tract repair.
    Wenxiu Ma, Zirong Zhao, Jialin Li, Bingqing Hu, Ke Liu, Jiajia Shen, Rong Yin, Jing Xie, Bitao Lu, Kun Yu, Fei Lu, Guangqian Lan, Ruiqi Xie, Enling Allen Hu, Wentao Lin, Qing Zhou.
      The effective repair of female reproductive tract (FRT) mucosal injuries is a significant clinical challenge, often hindered by the poor mechanical integrity and uncontrolled drug release profiles of conventional biomaterials. To address these limitations, a hierarchical "system-in-a-system" dressing, [CC@La]-$-[CP@F], was engineered entirely from natural polysaccharides. This integrated platform combines a mechanically robust primary scaffold with a secondary therapeutic delivery system. The primary scaffold, a fiber-reinforced sponge (CP@F), was fabricated via a pH-responsive Schiff base reaction between carboxymethyl chitosan and oxidized pullulan, followed by lyophilization. The incorporation of chitosan fibers resulted in a nearly three-fold increase in compressive strength to 348.97 kPa, transforming the fragile matrix into a resilient, load-bearing structure with excellent shape-memory and injectability. Embedded within this sponge are antioxidant (α-lipoic acid)-loaded microspheres (CC@La), engineered using Layer-by-Layer assembly. This dual-barrier architecture effectively suppresses burst release, enabling a sustained, multi-day therapeutic delivery specifically triggered by the acidic wound microenvironment (pH 5.5). The engineered composite demonstrated superior hemostatic efficacy in challenging in vivo models, including non-compressible liver hemorrhage, reducing bleeding time by over 55% compared to commercial gelatin sponges. Furthermore, the dressing exhibited potent, broad-spectrum antimicrobial activity (>99% efficacy) and antioxidant capacity. In a rat model of FRT mucosal injury, the multifunctional dressing significantly accelerated wound closure and promoted high-quality, regenerative healing, characterized by complete re-epithelialization and organized collagen deposition. This work presents a comprehensive engineering strategy, demonstrating how integrating mechanical reinforcement with programmed, multi-stage therapeutic action can orchestrate the entire wound healing cascade.
    Keywords:  Controlled drug release; Female reproductive tract repair; Fiber reinforcement; Hemostasis; Polysaccharide; Schiff base
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152592
  19. Biomaterials. 2026 May 05. pii: S0142-9612(26)00303-0. [Epub ahead of print]334 124279
    Spleen-tumor dual-targeting vaccines reshape anticancer landscape by activating both innate and adaptive immunity.
    Wenfei Xu, Xiaoyan Li, Wenqiang Hu, Jiaxin Zhou, Xing Liu, Jianbo Yu, Fan Zhang, Weidong Nie, Guihong Lu, Yanli Zhao.
      Owing to the reticular structure and dense lymphocyte concentration within the spleen, spleen-targeted vaccines can overcome the challenges faced by conventional vaccines, such as inefficient antigen delivery and delayed immune activation. However, the existing spleen-targeted vaccines are ineffective in preventing and treating immunologically cold tumors. Herein, we develop a spleen/tumor dual-target hybrid vaccine that combines red blood cell membrane-derived vesicles (RBCVs) and bacterial outer membrane vesicles (OMVs) to deliver tumor antigens. This hybrid vaccine utilizes RBCVs to enhance the biosafety of OMVs and endows them with a spleen-targeting ability. Co-delivery of OMVs as adjuvants with tumor antigens to the spleen triggers rapid and robust immune responses, promoting immune memory formation to prevent the development and metastasis of immunologically cold tumors. In addition to acting as vaccine adjuvants, OMVs can target and remodel the immunosuppressive tumor microenvironment by reprogramming tumor-associated macrophages and downregulating regulatory T cells, thereby enhancing the immune responses induced by vaccines and immune checkpoint inhibitors. Because of their antigen-loading flexibility, these versatile vesicles can be used for the spleen-targeted delivery of various protein- or nucleic acid-based antigens, offering a safe and promising strategy for the prevention and treatment of diverse tumors and pathogens.
    Keywords:  Bacterial outer membrane vesicles; Dual-targeting vaccines; Immune response; Red blood cell membrane-derived vesicles
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124279
  20. Discov Oncol. 2026 May 21.
    Advanced liposomal nanoplatforms for flavonoid delivery: a mechanistic and comparative perspective in hepatocellular carcinoma.
    Poonam Lal, Jitendra Patel.
      Hepatocellular carcinoma (HCC) is a common and life-threatening type of liver cancer, and its treatment results are frequently restricted by late diagnosis, drug resistance, systemic toxicity, and limited specificity of traditional treatment methods, including chemotherapy, surgery, and targeted therapy. Flavonoids, which are a family of naturally-occurring polyphenolic compounds, have been of significant interest in the past few years, based on their antioxidant and anti-inflammatory, anti-proliferative and pro-apoptotic characteristics. These compounds can control major signaling pathways related to tumor development and progression and are good candidates for the treatment of HCC. Poor aqueous solubility, high metabolism, and low bioavailability, however, greatly limit the clinical use of flavonoids. The delivery system of flavonoids based on liposomes is the possible solution to these restrictions as they preserve the stability, solubility, and tumor-targeting characteristics and protect the flavonoid against degradation, encasing it directly into a vesicle of phospholipid. The improvement of therapeutic performance has been implemented through various approaches to formulation, which are inclusive of thin-film hydration, PEGylation, ligand-mediated targeting, and stimuli-responsive systems. The review has provided the latest developments in liposomal delivery of flavonoids as a tool in the application of HCC which include formulation, physicochemical characterization, and therapeutic effects of flavonoids based on in vitro and in vivo experiments. It is also applied by giving a comparative study with conventional therapies. Moreover, such crucial issues about clinical translation as formulation stability, regulatory standards, expandability, and lack of clinical evidence are severely tackled. Lastly, the outlook of the future in the areas of targeted delivery, combination therapy, and clinical validation are described. In general, the liposomal delivery of flavonoids is a compelling approach to enhancing the therapeutic response of hepatocellular carcinoma.
    Keywords:  Flavonoids; Hepatocellular carcinoma; Liposomes; Nanocarriers; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s12672-026-05161-3
  21. Stem Cell Res Ther. 2026 May 21.
    HAMA microneedles patch loaded with Three-Dimensional exosome and Mupirocin promote diabetic wound healing.
    Ying Hu, Yu Wu, Yuansen Luo, Xiangkai Kong, Delong Zhu, Kunrui Wang, Xiang Lan, Lei Zhu, Tao Xu, Kun Wang.
      Diabetic wound healing impairment poses significant clinical challenges due to infection risks, poor angiogenesis, and chronic inflammation, often leading to amputation or death. Recently, mesenchymal stem cell-derived exosomes (Exos) exhibit potential in enhancing angiogenesis and suppressing inflammation, yet clinical application is limited by short half-life, low bioavailability, and high costs. Three-dimensional (3D) culture technology improves exosome yield and therapeutic efficacy, demonstrating superior performance in tissue regeneration. Concurrently, microneedle (MN) systems enable efficient transdermal drug delivery with minimal invasiveness. This study integrates 3d-Exo with Mupirocin into a hyaluronic acid methacrylate (HAMA)-based MN patch (3d-Exo MN) to enhance diabetic wound healing. The HAMA matrix ensures exosome stability and controlled release, while Mupirocin targets infection. In vitro and in vivo evaluations reveal that 3d-Exo MN significantly promotes cell proliferation, migration, and neovascularization, addressing key limitations of conventional therapies. By synergizing 3d-Exo advantages with MN-mediated delivery, this innovative platform offers a targeted, biocompatible strategy for diabetic wound management, bridging gaps in current treatment paradigms through enhanced drug efficacy and localized action.
    DOI:  https://doi.org/10.1186/s13287-026-04992-9
  22. Medicine (Baltimore). 2026 May 15. 105(20): e48829
    The potential of stem cells in breast cancer therapy: A review.
    Zundong Liu, Dachun Wang.
      Breast cancer remains the most prevalent malignancy among women worldwide, underscoring the urgent need for innovative therapeutic strategies. Stem cell-based anticancer approaches have attracted substantial attention because of their ability to generate immune-related cells and selectively home to tumor sites, among which mesenchymal stem cells (MSCs) are considered particularly promising owing to their strong tumor-tropic capacity and low immunogenicity. In this review, current evidence on the biological functions and therapeutic potential of MSCs and MSC-derived exosomes in breast cancer was systematically compiled and analyzed, with particular emphasis on MSC-mediated cytokine signaling, modulation of the tumor microenvironment, and the molecular cargo and functional effects of MSC-derived exosomes. The available data indicate that MSCs exert context-dependent dual effects, either promoting or inhibiting tumor growth through secretion of cytokines and activation of intercellular signaling pathways, while exosomes derived from MSCs likewise display both antitumor and protumor activities yet retain intrinsic tumor-targeting capability. Notably, compared with live MSCs, exosomes demonstrate greater stability, reduced immunogenic risk, and enhanced feasibility as therapeutic delivery vehicles, highlighting their translational potential. Accumulating evidence suggests that immune regulation and remodeling of the tumor microenvironment represent central mechanisms underlying these bidirectional effects. Collectively, MSCs and their derived exosomes constitute promising therapeutic platforms for breast cancer; however, their context-dependent regulatory properties necessitate rigorous mechanistic investigation and careful optimization prior to clinical application, and a deeper understanding of the molecular pathways through which they influence tumor progression will be essential for the development of safer and more effective stem cell-based anticancer therapies.
    Keywords:  MSC-derived exosomes; MSCs; breast cancer strategy; stem cells; underlying mechanisms
    DOI:  https://doi.org/10.1097/MD.0000000000048829
  23. BMC Mol Cell Biol. 2026 May 18.
    Hypoxia-pretreated exosomes promote enterocutaneous fistula healing via regulating inflammation and tissue repair.
    Yankui Liu, Beini Zhu, Hongbin Liu, Qingmei Yuan, Cong Yuan, Yijun Meng, Hong Zhou, Luming Sun, Beiyin Liu, Zhaoxiang Wu.
       BACKGROUND: Enterocutaneous fistula (ECF) is an abnormal pathological passage. This study aims to investigate the role and mechanism of action of gelatin sponges loaded with hypoxic exosomes (GS-Hypo-Exos) in the treatment of enterocutaneous fistulas.
    METHODS: A rat ECF model was established and subjected to intervention therapy, with the following groups: control group, gelatin sponge loaded with PBS group (GS-PBS), gelatin sponge loaded with hypoxia-exosomes group (GS-Hypo-Exos), and gelatin sponge loaded with normoxic exosomes group (GS-Nor-Exos). After 21 days of intervention, rat serum and perifistulous tissue were collected. Inflammatory response and collagen were analyzed via ELISA and histological staining. Flow cytometry determined macrophage phenotype proportions in fistula tissue. Immunofluorescence staining assessed angiogenesis. In vitro experiments further examined the effects of GS-Hypo-Exos on epithelial cell, fibroblast, endothelial cell, and macrophage function.
    RESULTS: The GS-Hypo-Exos group demonstrated the most significant fistula healing effect. This group exhibited the lowest serum IL-1β levels and the highest IL-10 levels. Histopathological analysis revealed reduced inflammatory cell infiltration and increased collagen deposition in fistula tissues following GS-Hypo-Exos treatment. Flow cytometry analysis revealed a significant increase in the proportion of M2 macrophages within the GS-Hypo-Exos group. Enhanced signaling of angiogenesis-related markers indicated increased mature vascular structures. In vitro experiments confirmed that GS-Hypo-Exos promoted HaCaT cell proliferation and migration, enhanced fibroblast collagen synthesis capacity, improved endothelial cell tube formation ability, and drove macrophage polarization toward the M2 phenotype.
    CONCLUSIONS: The GS-Hypo-Exos suppress inflammatory responses, enhance the function of key repair cells, promote collagen deposition and neovascularization, thereby creating conditions for fistula tissue repair.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Enterocutaneous fistula; Exosomes; Hypoxia; Macrophage polarization
    DOI:  https://doi.org/10.1186/s12860-026-00592-w
  24. J Transl Med. 2026 May 21.
    Human mesenchymal stem cell-derived miR-3614-5p exosomes suppress progression of colorectal cancer by targeting IL7Rα.
    Mengling Ye, Yingzhen Bian, Yanyan Lin, Shirong Li, Lixia Jiang, Jinlu Wu, Yuxuan Xie, Shufang Ning, Yuyang Liu, Jinglei Huang, Xinxing Lei, Litu Zhang.
       BACKGROUND: Colorectal cancer (CRC) represents a growing global health burden, particularly in developing countries. Mesenchymal stem cells (MSCs) have been reported to suppress tumor progression partly through the release of exosomes that deliver therapeutic molecules. However, the therapeutic potential of engineered MSC-derived exosomal microRNAs (Exo-miRNAs) in CRC remains largely unexplored.
    METHODS: Plasma exosome miRNA sequencing was performed to identify dysregulated miRNAs in CRC. Gain- and loss-of-function assays were conducted to evaluate the biological effects of candidate miRNAs in CRC cells. Human mesenchymal stem cells (hMSCs) were engineered to overexpress miR-3614-5p via Lipofectamine-mediated transfection, and exosomes enriched with miR-3614-5p were isolated and characterized. The effects of engineered hMSC-derived exosomal miR-3614-5p (Exo-miR-3614-5p) on CRC progression were assessed both in vitro and in vivo. Mechanistic studies were performed to identify downstream targets and signaling pathways.
    RESULTS: miR-3614-5p was identified as a therapeutic miRNA that was significantly downregulated in CRC. Engineered hMSCs efficiently loaded miR-3614-5p into secreted exosomes. Treatment with Exo-miR-3614-5p markedly suppressed CRC cell proliferation in vitro and inhibited tumor growth in vivo. Mechanistically, miR-3614-5p directly bound to the 3' untranslated region (3'UTR) of IL7Rα, resulting in translational repression and subsequent inactivation of the JAK2/STAT3 signaling pathway. In addition, miR-3614-5p exhibited potential diagnostic value for CRC.
    CONCLUSIONS: This study demonstrates that engineered hMSC-derived exosomal miR-3614-5p effectively inhibits CRC progression primarily through downregulation of IL7Rα and suppression of the JAK2/STAT3 signaling pathway. These findings suggest that Exo-miR-3614-5p represents a promising therapeutic and diagnostic candidate for CRC.
    Keywords:  Colorectal cancer; Exo-miR-3614-5p; Human mesenchymal stem cells; IL7Rα; JAK2/STAT3
    DOI:  https://doi.org/10.1186/s12967-026-07859-y
  25. Int J Nanomedicine. 2026 ;21 591179
    The Design Strategies and Applications of Engineered Nanoparticles for Traumatic Brain Injury.
    Chunyu Xiang, Yuhang Zhu, Xu Gao, Fengshuo Guo, Xiaodong He, Wenqi Luo, Wanguo Liu, Rui Gu.
      Traumatic brain injury (TBI) is a serious neurological condition. Because of its complex pathophysiological processes, direct treatment options are extremely limited. A key reason for this is the blood-brain barrier (BBB), which makes it difficult for conventional drug molecules to penetrate and maintain effective concentrations in brain tissue. In recent years, nanoparticles have garnered significant attention due to their unique biological properties, enhanced therapeutic effects, and low toxicity. By modifying the surface of nanoparticles with targeting ligands, their penetration capacity can be significantly enhanced, enabling directed delivery to the core injury area and substantially increasing their accumulation at the site of injury. Furthermore, functionally engineered nanoparticles can respond to specific signals in the TBI microenvironment, such as reactive oxygen species (ROS), enzymes, and pH changes, thereby enabling controlled drug release and significantly improving delivery efficiency. This review systematically summarizes the latest advances in engineered nanoparticles for TBI treatment from three perspectives: rational design, therapeutic strategies, and clinical translation.
    Keywords:  anti-inflammation; anti-oxidative stress; nanomedicine; nanoparticle; nanozyme; neurogenesis; neuroprotection; traumatic brain injury
    DOI:  https://doi.org/10.2147/IJN.S591179
  26. J Dent. 2026 May 20. pii: S0300-5712(26)00451-3. [Epub ahead of print] 106781
    Porous Phosphate Glass Microspheres Loaded with Dental Pulp Stem Cell - Derived Exosomes for Potential Osteogenic Applications.
    K G Aghila Rani, Savitha Suresh, Moustafa E Katamesh, Hamza M Al-Hroub, Kamis Gaballah, Md Towhidul Islam, Ifty Ahmed, Ensanya A Abou Neel.
       OBJECTIVE: This study investigated porous phosphate-based glass microspheres (PGMS) as a delivery system for human dental pulp stem cell (hDPSC)-derived exosomes (Exo) and examined their effects on osteogenic responses in human osteoblasts (HOB) in vitro.
    METHODS: PGMS (40P2O5-24MgO-16CaO-20Na2O) were produced by flame spheroidization and characterized by SEM-EDX and FTIR to confirm their porous architecture, oxide distribution, and phosphate network integrity. hDPSC-derived exosomes were isolated, quantified, and validated by STEM and western blotting for CD9, CD63, and CD81 expression. HOBs were treated with PGMS (1 mg/mL), Exo (10 µg/mL), or PGMS loaded with Exo (PGMS+Exo), and cell responses were evaluated by viability assays, qPCR, western blotting, ALP activity, and mineralization.
    RESULTS: Exo alone significantly enhanced HOB viability at 24 hours, which was further increased by PGMS+Exo. PGMS+Exo treatment yielded the highest expression of osteogenic genes (RUNX2, ALP, Col1, OC), elevated ALP activity, and greater mineral deposition and calcium release compared with PGMS or Exo alone. Western blotting further corroborated these findings.
    CONCLUSION: Exosome-loaded PGMS improved osteogenic outcomes in vitro compared with individual treatments, indicating their potential as a therapeutic platform for bone regeneration.
    CLINICAL SIGNIFICANCE: The results suggest that exosome‑loaded phosphate‑based microspheres may offer a regenerative approach for enhancing dental and craniofacial bone repair, although the findings are limited to in vitro experiments and require in vivo validation.
    Keywords:  Biomaterials; Exosomes; Human dental pulp stem cells (hDPSCs); Mineralization; Osteogenic differentiation; Porous phosphate-based glass microspheres (PGMS); Regenerative medicine
    DOI:  https://doi.org/10.1016/j.jdent.2026.106781
  27. Mini Rev Med Chem. 2026 May 11.
    Trends in Pain Relief in Cancer Patients: Pharmacotherapy and Medical Device Therapy.
    Rohit Sharma, Mohsina Patwekar, Faheem Patwekar, Nobendu Mukerjee, Jan Hruska, Lukas Peter, Subham Sarkar, Kamil Kuca.
      The landscape of cancer pain management has evolved significantly with advancements in pharmacological and medical device therapies, shifting focus from opioid reliance to a multimodal treatment approach. This strategy emphasizes the use of non-opioid medications, including NSAIDs, acetaminophen, and adjuvant analgesics such as gabapentin and pregabalin, particularly for managing neuropathic pain. The emerging field of pharmacogenomics enhances personalized pain management, tailoring treatments to individual patient responses to minimize adverse effects and optimize drug efficacy. Additionally, medical device therapies like intrathecal drug delivery systems, transcutaneous electrical nerve stimulation (TENS), and spinal cord stimulation (SCS) are gaining traction. These methods offer non-invasive options to reduce pain severity and opioid use, thus improving patient quality of life. Engineered exosomes carrying different drugs and inhibitors can also be administered in the tissue experiencing the pain and alleviate it. The integration of these innovative pharmacological and device-based therapies presents a future where cancer pain management is more effective, safer, and tailored to individual patient needs.
    Keywords:  Cancer pain; exosomes.; medical devices; neuromodulation; opioids; pharmacotherapy; targeted therapy
    DOI:  https://doi.org/10.2174/0113895575431374260420210102
  28. Research (Wash D C). 2026 ;9 1264
    Plant-Derived Extracellular-Vesicle-Like Particles: Immune Regulation and Disease Therapy.
    Hurong Shen, Qiwen Lu, Yueyi Huang, Jiaxin Jiang, Wenxi Chen, Wenrui Liu, Yanglin Qu, Jiankang Mu, Jing Chen, Lijun Jia, Xuan Han.
      Immune regulation is essential in both the pathogenesis and treatment of various diseases. Plant-derived extracellular-vesicle-like particles (PDEVLPs), especially herbal medicine, are emerging as promising cross-species nanotherapeutic carriers for immune regulation due to their intrinsic bioactive components. Compared with traditional small-molecule drugs, these natural nanocarriers offer superior pharmacokinetic properties in mammalian systems, including enhanced targeting capacity and penetration efficiency as well as prolonged circulation time. Due to the biogenic structures and low immunogenicity, most PDEVLPs exhibit generally favorable biocompatibility and substantial advantages in specific contexts. However, their immunological profile in humans, particularly the risk of immunogenicity from heterologous plant proteins, requires further investigation compared to established platforms such as liposomes. While diverse active ingredients endow PDEVLPs with effective regulation of various immune cells, they support body homeostasis and offer marked potential for treating multifactorial inflammatory and immune-related diseases. This review examines disease-specific immune microenvironments to provide a theoretical foundation for selecting PDEVLP-based therapies. It also evaluates engineering strategies to enhance the targeted delivery and therapeutic efficacy of these interkingdom mediators. By summarizing recent advancements, this review aims to guide the development of next-generation immune regulatory carriers tailored to specific microenvironments.
    DOI:  https://doi.org/10.34133/research.1264
  29. Antioxid Redox Signal. 2026 May 19. 15230864261449248
    ALKBH5-Mediated m6A Demethylation Stabilizes HMGB1 to Drive Hepatocyte Pyroptosis and Liver Injury in Heat Stroke: Targeting via Biomimetic Nanodelivery.
    Yanli Sun, Xiaolong Shu, Fei Guo.
       AIMS: Heat stroke causes life-threatening liver injury, but its molecular basis remains poorly understood. We investigated whether ALKBH5-mediated N6-methyladenosine (m6A) demethylation stabilizes Hmgb1 transcripts and promotes hepatocyte pyroptosis through the NLRP3 inflammasome. We also developed mesenchymal stem cell membrane-coated glycyrrhizic acid liposomes (MMGLs) as a targeted therapeutic strategy.
    RESULTS: RNA-seq of HS rat livers revealed significant enrichment of pyroptosis pathways, with ALKBH5 identified as a hub gene. Mechanistically, heat stress upregulated ALKBH5, which demethylated HMGB1 mRNA, preventing its degradation and enhancing transcript stability. This stabilization led to increased intracellular High-mobility group box 1 (HMGB1) abundance, nucleocytoplasmic translocation, and extracellular release, subsequently activating the NLRP3-Caspase-1-GSDMD axis. Alkbh5 knockdown shortened Hmgb1 half-life and attenuated pyroptosis, whereas HMGB1 supplementation restored it. To target this axis, we engineered MMGLs (encapsulation efficiency: 81.7%), which exhibited superior inflammatory homing compared to unmodified liposomes. In HS rats, MMGLs achieved rapid hepatic accumulation, significantly reduced serum alanine aminotransferase/aspartate aminotransferase, and suppressed Interleukin-1 beta (IL-1β)/IL-18. MMGLs restored redox homeostasis by decreasing reactive oxygen species/malondialdehyde and boosting reduced glutathione/superoxide dismutase, thereby preserving hepatocyte architecture and inhibiting pyroptosis.
    INNOVATION: This study identifies an epitranscriptomic mechanism in HS-induced liver injury, in which ALKBH5-dependent stabilization of Hmgb1 mRNA amplifies pyroptotic signaling. MMGLs provide a biomimetic nanotherapeutic strategy to interrupt this inflammatory cascade.
    CONCLUSION: ALKBH5-mediated m6A demethylation stabilizes HMGB1 to drive hepatocyte pyroptosis during HS. MMGLs effectively target this axis, offering a promising therapeutic approach for acute liver damage. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  ALKBH5; HMGB1; heat stroke; m6A demethylation; nanodelivery; pyroptosis
    DOI:  https://doi.org/10.1177/15230864261449248
  30. Int J Nanomedicine. 2026 ;21 607870
    Organelle-Targeted Nanotherapeutics for Parkinson's Disease: From Pathogenesis to Preclinical Strategies and Translational Challenges.
    MaoYu Liu, QiWei Peng, Heng Zhai, Yi Wu, ZhuoRan Ma, ZhiCheng Tang, Haoxuan Ouyang, An Chang, XueBing Cao, Yan Xu, Yun Xia.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the aggregation of αSynuclein (αSyn). Organelle dysfunction is recognized as a central driver of pathological feature. Current treatments primarily alleviate symptoms but fail to halt disease progression, largely due to the inability to target the underlying subcellular pathology. This narrative review examines the emerging potential of organelle-targeted nanotherapeutics as a precision medicine strategy for PD treatment. We discuss how engineered nanoparticles can be designed to deliver therapeutics specifically to dysfunctional mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus, and nuclei. These approaches aim to interfere with key pathological mechanisms ameliorating oxidative stress, mitigating protein misfolding, restoring protein homeostasis, and modulating gene expression. We provide a comprehensive overview of recent preclinical advances in nanoparticles design, targeting mechanisms, and therapeutic efficacy. Furthermore, we critically evaluate the current challenges, including delivery efficiency, safety, reproducibility, storage, and large-scale translation before clinical application This review aims to provide a potential route toward disease-modifying nanotherapeutics for PD.
    Keywords:  Parkinson’s disease; drug delivery system; nanomedicine; organelle targeting
    DOI:  https://doi.org/10.2147/IJN.S607870
  31. Drug Des Devel Ther. 2026 ;20 601248
    Therapeutic Targets, Pharmacological Mechanisms, and Delivery Strategies for Diabetic Peripheral Neuropathy.
    Fanjing Wang, Chuqiao Shen, Weizhen Guo, Junyu Wang, Jinghui Xie, Guoming Shen, Yixuan Lin.
      With the global diabetes population projected to reach 783 million by 2045, diabetic peripheral neuropathy (DPN) remains a common and debilitating complication characterized by metabolic stress, inflammation, and microvascular dysfunction. This review summarizes current interventions for DPN from the perspective of therapeutic targets, pharmacological mechanisms, and emerging delivery strategies. Conventional pharmacotherapy mainly provides symptomatic relief; first-line analgesics such as duloxetine and pregabalin offer only moderate benefit, with a number needed to treat of approximately 4-5. Natural products, including resveratrol, ginkgo biloba, and tanshinone IIA, show antioxidant and anti-inflammatory potential, although supporting evidence remains largely preclinical. Emerging targeted therapies and nanocarrier-based delivery systems may improve disease modification and drug bioavailability. Overall, DPN treatment remains limited by the lack of disease-modifying therapies, insufficient high-quality clinical evidence, and major translational barriers. Future priorities include mechanism-based stratification, combination strategies, and rigorous trials incorporating objective and patient-reported outcomes.
    Keywords:  diabetic peripheral neuropathy; drug delivery; natural products; targeted therapy; therapeutic targets
    DOI:  https://doi.org/10.2147/DDDT.S601248
  32. J Nanobiotechnology. 2026 May 16.
    Hydrogel delivery platform of engineered apoptotic vesicles for ischemic stroke therapy.
    Dongdong Xiao, Yin Shen, Jinlu Gan, Shuang Li, Xiaobing Jiang, Haijun Wang, Qiangping Wang.
      Ischemic stroke, induced by the occlusion of cerebral blood vessels, represents a leading cause of global morbidity and mortality. Although thrombolytic therapy and mechanical thrombectomy are cornerstone treatments for restoring cerebral perfusion, their clinical effectiveness is severely constrained by a narrow therapeutic window. This study presents a reactive oxygen species (ROS) - responsive hydrogel platform loaded with engineered apoptotic vesicles (apoVs) designed to simultaneously target multiple post-stroke pathological processes. Proteomic analyses reveal that apoV isolated from apoptotic neural stem cells are enriched in proteins associated with angiogenesis and neuroprotection. In vitro investigations and in vivo animal experiment further demonstrate that the hydrogel can alleviate oxidative stress, promote angiogenesis and protect nerve injury by releasing hydrogen sulfide (H2S) - functionalized apoV in the infarct area. In summary, this hydrogel platform holds considerable therapeutic promise by transforming the hostile post-stroke microenvironment into a regeneration-permissive niche, thereby fostering endogenous tissue repair.
    Keywords:  ApoVs; H2S; Hydrogel; Stroke
    DOI:  https://doi.org/10.1186/s12951-026-04519-7
  33. Bioact Mater. 2026 Oct;64 212-231
    Reconstructing protein conformations to activate follicular enzyme-nutrient reservoirs for reversing follicle aging.
    Shifeng Ling, Mingyue Liu, Chen Meng, Kaifeng Huo, Yida Wang, Yixiang Zhang, Yingying Wei, Lucia Zhou, Yawei Du, Wenguo Cui.
      Hair regeneration depends on a reservoir of follicular enzymes that regulate the microenvironment and provide metabolic support. However, in degenerative alopecia, this enzymatic reservoir is disrupted, impairing microenvironmental homeostasis. Here, through bioinformatics and molecular dynamics analyses, we revealed that several Zn2+/Cu2+-dependent proteases (e.g., LOX and SOD1) were downregulated and exhibit aberrant conformations and activities in degenerative alopecia, further weakening microenvironmental support. To address this, we developed a Zn2+/Cu2+-doped decellularized extracellular matrix microneedle patch (dECMMAZn/Cu) to rapidly restore the follicular microenvironment and enzymatic reservoir function. In vitro, microneedle delivery of dECMMAZn/Cu significantly upregulated key Zn2+/Cu2+-dependent proteases. Restoration of the enzymatic reservoir reduced p16 expression in dermal papilla stem cells, inhibited cellular senescence, and promoted stem cell proliferation. In a classical degenerative alopecia animal model, dECMMAZn/Cu microneedle treatment resulted in denser and more continuous dermal collagen, a significant increase in hair follicle numbers, and promoted hair regeneration. In summary, this study establishes an innovative microneedle material that restores follicular function by remodeling protein conformation and activating the enzymatic reservoir.
    Keywords:  Decellularized matrix; Follicular aging; Microenvironmental homeostasis; Microneedle patch; Protein conformation
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.04.038
  34. ACS Appl Mater Interfaces. 2026 May 19.
    Exosome-Coated Boron-Containing Evodiamine Derivative Triggered by Pathology-Specific Reactive Oxygen Species Targets Myofibroblasts to Ameliorate Hypertrophic Scarring.
    Futing Shu, Hongchao Huang, Hua Sun, Ziyu Fang, Wenfeng Wu, Zixuan Zhou, Chunquan Sheng, Huazhen Liu, Shichu Xiao, Shanchao Wu, Yongjun Zheng.
      Targeting overactivated myofibroblasts is a potential treatment for hypertrophic scarring. Evodiamine, an indole alkaloid derived from Evodiae fructus, has attracted increasing attention for its antitumor efficacy to inhibit proliferation and promote apoptosis of tumor cells. However, its role on hypertrophic scarring remains unexplored. Hence, we engineered a boronic acid-functionalized evodiamine derivative (BED) triggered by pathology-specific reactive oxygen species (ROS) to target myofibroblasts to ameliorate hypertrophic scarring with minimal toxicity to normal fibroblasts. In vitro experiments presented that BED could be triggered by the increased ROS in myofibroblasts and thus selectively induce apoptosis and suppress proliferation of myofibroblasts, inhibit myofibroblast contraction and migration, and suppress α-SMA and collagen expression. The underlying antiscar mechanism was partly mediated by disrupting microtubules and microfilaments, thereby suppressing the proliferation and contraction of myofibroblasts. To optimize delivery and therapeutic efficacy, the exosome-encapsulated delivery system was further developed, and the results showed that exosomes-coated BED, enhancing BED cellular internalization while protecting BED from extracellular ROS degradation, achieved the optimized therapeutic efficacy of hypertrophic scarring in vivo by targeting myofibroblasts. This approach represents a promising therapeutic strategy for hypertrophic scarring and other fibrotic pathologies.
    Keywords:  borate unit; evodiamine; exosome; hypertrophic scar; myofibroblast; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsami.6c03628
  35. bioRxiv. 2026 May 06. pii: 2026.05.02.722401. [Epub ahead of print]
    Multispecific nanobody degraders co-deplete membrane receptors and enable targeted delivery of diverse payloads.
    Md Kabir, Yong Joon Jeffrey Kim, Zhijie Deng, Yufei Xiang, Paul R Sargunas, Nuozi Song, Zishan Wang, Nesteene J Param, Changzhong Jin, Zhe Sang, Alicia Yue, Alba Bundo, Razeen Hossain, Yue Zhong, Yindan Lin, Yan Xiong, Ernesto Guccione, Kuan-Lin Huang, Mingye Feng, Jian Jin, Yi Shi.
      Targeting membrane receptors underlies the success of antibody-drug conjugates (ADCs), yet single-receptor formats can be limited by heterogeneous expression, compensatory signaling, and variable internalization. Here we developed Multivalent Interchangeable Nanobody Degradation System (MINDS), a modular nanobody-Fc chassis that co-engages multiple membrane receptors, promotes their lysosomal co-depletion, and enables delivery of diverse intracellular payloads. As a proof of concept, we generated Tritazumab, a trispecific nanobody-Fc targeting three oncogenic receptors EGFR, cMET, and TfR1. Tritazumab incorporates a high-affinity, non-transferrin-competing anti-TfR1 nanobody that drives efficient uptake and lysosomal trafficking, enabling coordinated depletion of all three receptors. Across non-small cell lung cancer models, Tritazumab achieved rapid and sustained multi-receptor surface loss with picomolar degradation potency, reaching near-maximal depletion within approximately 1.5 hours. Conjugation of Tritazumab to MMAE preserved receptor binding and produced substantially greater antiproliferative activity and improved tumor selectivity relative to clinical ADCs in matched cell models, along with potent in viv o tumor growth inhibition and acceptable tolerability in a xenograft model. Extending the platform beyond cytotoxic payloads, a BRD4 molecular glue conjugate improved the selectivity window by > 100-fold and showed marked in vivo efficacy, while an EZH2-targeting PROTAC conjugate achieved an approximately 1,000-fold increase in intracellular degradation potency relative to the free PROTAC. These findings establish MINDS as a modular multispecific degrader-payload platform that integrates receptor co-depletion to enhance anticancer selectivity and efficacy.
    DOI:  https://doi.org/10.64898/2026.05.02.722401
  36. J Agric Food Chem. 2026 May 22.
    Differential Modulation of Colonic Inflammaging by Limonin Loaded in Pectin Emulsion Gels with Engineered Fine Structures.
    Wei-Yun Zhang, Jin-Song Liao, Jun-Ru Qi.
      The emulsion gel (EG) system offers an effective strategy to improve limonin bioavailability, yet the differential intervention targets of limonin-loaded EGs constructed from pectins with distinct fine structures in colonic inflammaging remain unclear. In this study, three structurally distinct pectin-based EGs were engineered by modulating the degree of esterification and rhamnogalacturonan-I side-chain ratio. In d-galactose-induced aged mice, these EGs exhibited superior anti-inflammatory effects against colonic inflammaging compared to free limonin with distinct functional preferences. LMLRGI-EGL enhanced chemical and mechanical barriers and LMHRGI-EGL inhibited the pyroptosis pathway. In contrast, LMHRGI-EGL exhibited the broadest inhibitory effect on the pyroptosis signaling pathway, significantly ameliorating damage to the colonic immune barrier. Meanwhile, HMLRGI-EGL uniquely enriched the relative abundance of Erysipelotrichaceae and effectively suppressed the expression of the inflammatory cytokines. These findings demonstrate that structural variations in EGs enable differential regulation of colonic inflammaging through structure-dependent mechanisms.
    Keywords:  colonic inflammaging; emulsion gel; limonin; pectin
    DOI:  https://doi.org/10.1021/acs.jafc.6c01910
  37. Biotechnol Bioeng. 2026 May 21.
    Metabolic Engineering Strategies for Flavonoid Biosynthesis in Saccharomyces cerevisiae: Current Advances and Future Perspectives.
    Xu Cheng, Mengnan Han, Guogeng Zhang, Weibo Qiao, Lei Wang, Yong Ma.
      Flavonoids are a class of plant secondary metabolites with diverse physiological activities, including antioxidant and anti-inflammatory effects. Growing demand for these compounds now exceeds the capacity of traditional plant extraction methods. Advances in the elucidation of flavonoid biosynthetic pathways, combined with progress in synthetic biology, have enabled the use of engineered microorganisms for sustainable flavonoid production. Saccharomyces cerevisiae, with its well-developed genetic toolkit, high safety profile, and eukaryotic protein modification machinery, has emerged as an ideal chassis for the heterologous biosynthesis of flavonoids. This review systematically outlines the structural classification and biosynthetic pathways of flavonoids, summarizes recent advances in pathway reconstruction, and provides a quantitative comparison of metabolic engineering strategies in S. cerevisiae. We further discuss the key bottlenecks that currently hinder scale‑up from laboratory flasks to industrial bioreactors and propose that future research should focus on intelligent regulatory systems. When combined with rational design of metabolic networks and microbial consortia, such systems can enable adaptive balancing between growth and product synthesis under industrial-scale environmental fluctuations. Collectively, these intelligent engineering strategies will advance S. cerevisiae as an efficient and scalable platform for flavonoid biomanufacturing.
    Keywords:  Saccharomyces cerevisiae; co‐culture; flavonoids; industrialization; metabolic engineering
    DOI:  https://doi.org/10.1002/bit.70248
  38. Antiinflamm Antiallergy Agents Med Chem. 2026 May 15.
    Immunomodulatory Nanocarriers in Multiple Sclerosis: Dual Targeting of Microglia and Mitochondria for Precision Neurotherapy.
    Ayushi Bhandari, Shikha Baghel Chauhan, Indu Singh, Chirag Jain.
      The chronic neuroinflammatory and neurodegenerative disease known as Multiple Sclerosis (MS) is characterized by mitochondrial dysfunction and ongoing microglial activation. Developments in nanomedicine have enabled the design of immunomodulatory nanocarriers that target mitochondria and microglia simultaneously, thereby addressing two key pathogenic characteristics. By delivering antioxidants and anti-inflammatory drugs straight to microglia and their mitochondria, these systems increase the effectiveness and specificity of treatment. This review summarizes preclinical research on nanocarriers for delivery to the central nervous system, including liposomes, polymeric nanoparticles, dendrimers, amphiphilic polymer nanoparticles, and modified exosomes, for the years 2020-2025. Functionalized liposomes containing microglia-specific peptides or Toll-like receptor 4 ligands can boost microglial uptake by up to five times, which causes cells to adopt anti-inflammatory characteristics. By incorporating antioxidants such as coenzyme Q₁₀ and N-acetylcysteine, and by using polymeric nanoparticles with mitochondrial- targeting groups, such as triphenyl phosphonium, these nanoparticles improve blood-brain barrier penetration and restore mitochondrial function. Dendrimers and exosomes facilitate effective intracellular and mitochondrial transport, reducing oxidative stress and inflammatory signaling, whereas amphiphilic polymer nanoparticles target scavenger receptors to decrease protein aggregation and neuroinflammation. In MS models, dual-targeting nanocarriers that combine mitochondrial repair and microglial modulation exhibit synergistic neuroprotective effects. Even with promising preclinical findings, there are still obstacles to overcome to achieve clinical translation, scale up production, and ensure long-term safety. Early microglial modulator experiments using sophisticated delivery devices show promise. Finally, dual-targeting immunomodulatory nanocarriers present a new precision neurotherapy strategy for multiple sclerosis. Sustained improvement of clinical pathways, safety, and pharmacokinetics may revolutionize therapeutic approaches and enhance patient outcomes.
    Keywords:  Multiple sclerosis; dual-targeted delivery systems; immunomodulatory nanocarriers; liposomes.; microglia targeting; mitochondrial dysfunction
    DOI:  https://doi.org/10.2174/0118715230437703251219204750
  39. Mol Ther Oncol. 2026 Jun 18. 34(2): 201197
    Engineering precision oncology: Targeting tumors and immune cells with lentiviral vectors.
    Julia Rossi, Chiara Martinello, Riccardo Sorrentino, Véronique Guyonnet-Duperat, Samuel Amintas, Maria Jimena Abrey Recalde, Els Verhoeyen, Sandrine Dabernat.
      Lentiviral vectors (LVs) are emerging as versatile tools for the efficient and stable delivery of therapeutic genes. Although VSV-G-pseudotyped LVs remain the standard for ex vivo genetic engineering, their broad tropism and serum sensitivity limit their applicability for in vivo cancer therapy, where precise targeting is essential for efficacy and safety. This review synthesizes two decades of advances in LV pseudotyping, comparing natural viral envelopes, engineered targeting strategies, and multicomponent glycoprotein systems that reshape vector tropism. We discussed donor-derived envelopes such as measles virus, baboon endogenous retrovirus, Nipah virus, and Sindbis virus, highlighting their value for transducing hematopoietic, immune, and tumor cells. We also examined next-generation retargeting innovations, including engineered receptor-binding domains, display of cytokines or antibody fragments, and VSV-G mutants that ablate natural receptor interactions, to enhance specificity for T cells, B cells, hematopoietic stem cells, and tumor-associated antigens. Finally, we review the recent emergence of engineered virus-like particles (VLPs) as precision tools for in vivo delivery of CRISPR-Cas9, base-editing, and prime-editing complexes. Collectively, these advances position receptor-targeted lentiviral and VLP systems as promising platforms for the next generation of precision oncology, enabling selective in vivo CAR T/NK cell generation, targeted tumor modification, and cell-restricted gene editing.
    Keywords:  LV pseudotyping; MT: Regular Issue; Sindbis virus; VSV-G; cancer therapy; immunity; in vivo gene therapy; lentiviral vector; paramyxovirus; tumor targeting
    DOI:  https://doi.org/10.1016/j.omton.2026.201197
  40. Integr Cancer Ther. 2026 Jan-Dec;25:25 15347354261450965
    Combination Therapy of Sini Decoction and Cyclophosphamide Inhibits Tumor Growth in an Orthotopic Lung Cancer Model.
    Dacheng Pang, Shuo Zhang, Tian Tian, Tong Wang.
       BACKGROUND: Lung cancer represents a frequently seen respiratory system malignancy. Sini Decoction combined with cyclophosphamide is demonstrated to remarkably extend survival and improve quality of life of these patients; however, the associated anti-tumor mechanisms are largely unexplored.
    OBJECTIVE: The present work focused on investigating the inhibition of tumor cells by Sini Decoction plus cyclophosphamide within the orthotopic lung cancer model and exploring the mechanisms in terms of exosome-based tumor hypoxic microenvironment modulation.
    METHODS: A549-luc2-tdT-2 cells were implanted in left lung of nude mice for establishing the orthotopic lung cancer xenograft model. After 5 days, bioluminescence imaging was conducted for model validation. Mice were later randomized as 4 groups: model, Sini Decoction, cyclophosphamide, as well as Sini Decoction plus cyclophosphamide. Bioluminescence imaging was conducted to assess anti-tumor effects. Enzyme-linked immunosorbent assay (ELISA) was performed for measuring liver and kidney function indicators (ALT, AST, Cr) in serum. Additionally, RT-qPCR and immunohistochemistry were carried out for detecting hypoxia-related factor levels (HIF-1α, VEGF, PDGF-β) within lung tissue. Additionally, characterizations of the separated exosomes were completed with transmission electron microscopy, BCA protein assay, nanoparticle tracking analysis, and Western blotting. Exosomal miR-20a-5p was chosen based on TargetScan database for analysis, while RT-qPCR was completed for validation.
    RESULTS: Sini Decoction plus cyclophosphamide dramatically suppressed tumor growth within the orthotopic lung cancer model while ameliorating hepatorenal toxicities, as evidenced by serum liver and kidney function indicators and bioluminescence imaging. Meanwhile, immunohistochemistry showed that the combination therapy markedly downregulated HIF-1α expression in lung tissue and suppressed the expression of its downstream target genes VEGF and PDGF-β, which was also confirmed by RT-qPCR. Additionally, bioinformatic analysis suggested that tumor-derived exosomal miR-20a-5p could target HIF-1α. Isolation and RT-qPCR analysis of lung tissue-derived exosomes demonstrated that the combination therapy significantly downregulated the expression of exosomal miR-20a-5p.
    CONCLUSION: This study indicates that the combination of Sini Decoction and cyclophosphamide can effectively inhibit lung cancer growth and alleviate hepatorenal toxicity. The mechanism may be associated with the amelioration of the tumor hypoxic microenvironment, inhibition of the HIF-1α-mediated tumor hypoxia signaling pathway, and regulation of exosomal miR-20a-5p expression.
    Keywords:  cyclophosphamide; exosomes; lung cancer; sini decoction; tumor hypoxic microenvironment
    DOI:  https://doi.org/10.1177/15347354261450965
  41. Biomacromolecules. 2026 May 22.
    Dual-Gene CRISPR Editing via Peptide Dendrimers Regulates Redox Balance for Diabetic Wound Repair.
    Yuhang Jiang, Haobo Wen, Jiaqi Xu, Wanjia Peng, Jie Zhou, Hongli Mao, Zhongwei Gu, Yiyan He.
      The management of chronic diabetic wounds, plagued by persistent oxidative stress, remains a major clinical challenge. We devised a CRISPR/Cas9-based gene therapy to fundamentally reprogram this pathological microenvironment. A single system was engineered for the simultaneous knockdown of Keap1 and PHD2, key negative regulators of the Nrf2 and HIF-1α pathways, respectively. This payload was delivered by multifunctional peptide-modified lysine dendrimers (MsRNPs), which self-assembled into stable, positively charged nanoparticles that effectively complexed with DNA. The MsRNPs showed excellent biocompatibility and mediated efficient cellular uptake and gene editing in vitro, leading to reduced ROS levels. Consequently, a single topical application of the polyplexes in a diabetic mouse model robustly accelerated wound closure, enhanced collagen deposition, and promoted angiogenesis, driven by the synergistic activation of Nrf2 and HIF-1α. This study establishes a novel combinatorial gene-editing strategy and a versatile nanoplatform for treating oxidative stress-related pathologies.
    DOI:  https://doi.org/10.1021/acs.biomac.6c00110
  42. 3 Biotech. 2026 Jun;16(6): 201
    Beyond antibiotics: innovative and translational strategies to overcome antimicrobial resistance.
    Anu Kumar, Bhanu Krishan, Sunny Dhiman, Anupam Sharma, Varsha Thadiyan, Wamik Azmi.
      The rapid rise of antimicrobial resistance demands therapeutic strategies that extend beyond conventional antibiotics. However, most existing reviews describe emerging alternatives without systematically linking their mechanistic advances to translational readiness and clinical implementation barriers. This review addresses this gap by integrating evidence across multiple beyond-antibiotic approaches, including antimicrobial peptides, bacteriophage therapy, CRISPR-based antimicrobials, nanotechnology-enabled delivery systems, anti-virulence agents, host-directed immunotherapies, microbiome modulation (engineered probiotics and fecal microbiota transplantation), and drug-repurposing or combination therapies. The principal contribution of this synthesis is a comparative framework that maps mechanisms of action, engineering innovations, and translational evidence across these diverse strategies. Advances such as peptidomimetics, engineered phages, and nanoparticle carriers that enhance stability, targeting, and therapeutic efficacy are highlighted, along with synergistic strategies including phage-antibiotic and CRISPR-nanocarrier combinations. The review further identifies major barriers limiting clinical translation, including delivery efficiency, toxicity and ecological concerns, large-scale production challenges, cost, inconsistent clinical outcomes, and regulatory fragmentation for biologics and live therapeutics. To facilitate clinical implementation, the study proposes a translational roadmap emphasizing standardized evaluation assays, physiologically relevant infection models, integrated rapid diagnostics, and regulatory frameworks tailored for emerging antimicrobial platforms, thereby supporting the development of sustainable therapies for the post-antibiotic era.
    Keywords:  Antimicrobial resistance; CRISPR-Cas antimicrobials; antimicrobial peptides; bacteriophage therapy; host-directed therapies; microbiome modulation; nanotechnology; non-antibiotic therapies; translational medicine
    DOI:  https://doi.org/10.1007/s13205-026-04836-6
  43. Biomed Microdevices. 2026 May 04. pii: 39. [Epub ahead of print]28(2):
    Porous GelMA microneedle with delivery of AIE molecules via HSF-derived exosomes for hypertrophic scar treatment.
    Zeming Liu, Lingbo Zhang, Bo Yuan, Shuyi Wei, Meng Lyu.
      Hypertrophic scarring (HS) occurs after surgery or wounding, leading to tissue dysfunction and damaging the appearance. However, no satisfactory treatment strategy is available because the demand for eliminating hypertrophic scar fibroblasts (HSFs) in HS remains unfulfilled. Here, aggregation-induced emission molecule (TTMN)-based porous gelatin methacryloyl microneedles (MNs) were fabricated. The TTMNs were encapsulated in HSF-derived exosomes, which were subsequently assembled in the MN patch. This MN patch exhibited good biocompatibility. When the porous MN patch was applied to the HS, it released exosome-encapsulated TTMN (TE) in the deep skin tissue, triggering a burst of abundant reactive oxygen species in the HS under light irradiation. This event led to marked inhibition of the proliferation and migration of HSFs and collagen deposition in these cells. The application of TE-loaded porous MN patches significantly prevented HS formation in the New Zealand rabbit model of HS, as evidenced by a remarkable decrease in the scar elevation index and collagen I deposition. Thus, this study offers a feasible, convenient, and effective strategy for applying aggregation-induced emission-encapsulated HSF-derived exosome-based porous MNs for the treatment of fibrotic skin diseases.
    Keywords:  AIE; Exosomes; Hypertrophic scarring; Microneedle patches; Photodynamic therapy
    DOI:  https://doi.org/10.1007/s10544-026-00820-2
  44. ACS Mater Au. 2026 May 13. 6(3): 642-656
    Advancing Parkinson's Prevention: Brain-Specific Lipopolyplex Delivery of the GDNF as a Neuroprotective Gene Therapy.
    Yujing Zhang, Yujing Huang, Zhonghua Lu, Zhen Yuan.
      Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss. Although the glial cell line-derived neurotrophic factor (GDNF) offers therapeutic promise, its clinical translation is hampered by challenges related to delivery methods and the timing of intervention. Here, we developed a brain-targeted lipopolyplex (BAGLPP) for systemic GDNF gene delivery. BAGLPP incorporates an RVG29 peptide-modified lipid shell for blood-brain barrier crossing and a polyethylenimine-condensed AAV plasmid core for efficient transfection. Following intravenous administration, BAGLPP demonstrated superior brain accumulation and expression in PD-relevant regions. In a cellular PD model, BAGLPP pretreatment reduced apoptosis, oxidative stress, and pathological α-synuclein (pS129) accumulation. In MPTP-induced mice, prophylactic BAGLPP treatment established sustained GDNF expression (maintaining levels 3.7-fold higher than controls at 8 weeks postlesion), which activated the PI3K/Akt pro-survival pathway, suppressed pro-apoptotic Bax, and attenuated neuroinflammation. This multifaceted protection preserved dopaminergic neurons and striatal dopamine and improved motor function without significant systemic toxicity. Our findings establish BAGLPP as a durable, nonviral gene therapy platform with strong potential for preventing PD progression.
    Keywords:  Parkinson’s disease; brain targeting; gene therapy; glial cell line-derived neurotrophic factor; lipopolyplex
    DOI:  https://doi.org/10.1021/acsmaterialsau.6c00024
  45. Stem Cell Res Ther. 2026 May 20.
    Targeting skin barrier repair: mechanisms of action, therapeutic evidence, and clinical translation challenges of mesenchymal stem cell-derived exosomes.
    Yujin Li, Jian Huang, Zhibing Fu, Lihua Gao, Xiaoliang Tong, Lu Zhou, Jinrong Zeng, Lina Tan.
      Dysfunction of the skin barrier is a central pathological feature in dermatology, driving the need for innovative repair strategies. Mesenchymal stem cell-derived exosomes (MSC-exos) represent a promising cell-free therapeutic paradigm, leveraging their innate cargo to modulate regeneration and immune responses. This review systematically examines the multifaceted role of MSC-exos in restoring skin barrier integrity. We delineate their molecular mechanisms in repairing physical, immunological, and microbial barrier components, supported by evidence from preclinical disease models. The influence of MSC source and preconditioning on exosome efficacy is analyzed, alongside emerging bioengineering approaches. Crucially, we identify and discuss the key translational challenges-including standardization, scalable manufacturing, and regulatory pathways-that must be addressed to advance these nanotherapeutics toward clinical application. This synthesis provides a critical framework for future research aimed at harnessing MSC-exos for targeted barrier repair.
    Keywords:  Cell-free therapy; Clinical translation; Mesenchymal stem cell-derived exosomes; Skin barrier repair; Skin homeostasis
    DOI:  https://doi.org/10.1186/s13287-026-04941-6
  46. Cureus. 2026 Apr;18(4): e107198
    Topical Application of Human Umbilical Cord-Derived Mesenchymal Stem Cell Exosomes for a Deep Second-Degree Scald Burn Wound: A Case Report.
    Connie Zhi-Chen Hung, Tsai-Hua Chung, Wen-Hsien Lin.
      Conventional treatments for deep second-degree scald burns are frequently associated with prolonged healing times and hypertrophic scarring. Exosomes derived from mesenchymal stem cells represent a promising cell-free therapeutic strategy owing to their capacity to promote tissue regeneration. This report describes a 46-year-old woman with an unremarkable medical history who sustained a deep burn to her left thigh. The injury, classified as deep second-degree per American Burn Association (ABA) standards and involving 1% of the total body surface area (TBSA), significantly hindered her daily activities. Although not life-threatening, the localized pain and wound extent caused substantial functional impairment. Following one week of standard wound care without significant clinical improvement, a topical formulation containing human umbilical cord-derived mesenchymal stem cell exosomes (UC-MSC-Exos; ExoVia, BIONET Therapeutics Corp., Taipei, Taiwan) was applied once daily for nine consecutive days. Progressive granulation tissue formation and accelerated re-epithelialization were observed throughout the treatment period. Complete wound closure was achieved by day 18 post-injury, and the one-month follow-up demonstrated excellent skin quality with minimal scarring. No adverse reactions occurred during the treatment course. These preliminary findings suggest that topical application of UC-MSC-Exos could potentially serve as a well-tolerated adjunctive therapy associated with favorable healing for deep second-degree scald burns. Further investigation through larger, controlled clinical trials is warranted to validate these preliminary observations.
    Keywords:  case report; cell-free therapy; exosomes; mesenchymal stem cells; scald burn; wound healing
    DOI:  https://doi.org/10.7759/cureus.107198
  47. ACS Nano. 2026 May 19.
    Engineered 3D-Lattice Microneedle Array Patches for Enhanced Nanovaccine Delivery to Dendritic Cells in Cancer Immunotherapy.
    Ye Eun Kim, Jean Won Kwak, Xin Wang Mo, Thanh Loc Nguyen, Netra Unni Kamat, Ngoc Man Phan, Hyunsu Shin, Hyongsok Tom Soh, Joseph M DeSimone, Jaeyun Kim.
      Cancer vaccines are designed to activate dendritic cells (DCs), which are potent antigen-presenting cells that initiate antigen-specific adaptive immune responses and inhibit tumor growth. Microneedles (MNs) have emerged as a promising cancer vaccine platform, enabling the noninvasive dermal delivery of cancer antigens and adjuvants to activate dermal DCs. However, conventional solid MNs have a limited surface area, restricting the adsorption of large amounts of bioactive components. Therefore, 3D-printed lattice-structured microarray patches (L-MAPs) with an increased surface area were designed in this study, which permitted the enhanced adsorption of cancer nanovaccines compared to conventional solid microarray patches. L-MAPs were fabricated by using the continuous liquid interface production (CLIP) technology, facilitating the rapid printing of MNs with lattice structures. L-MAPs adsorbed higher amounts of mesoporous-silica-based nanovaccine (MV) on their needle surfaces, exhibiting greater dermal vaccine delivery capacity. Applying MV@MAPs on mouse skin led to efficient DC recruitment, maturation, and subsequent antigen-specific T cell responses in vivo. Consequently, the resulting antitumor immune response considerably suppressed the tumor growth. This approach highlights that using CLIP-printed L-MAPs is a promising strategy for efficient nanovaccine delivery in cancer immunotherapies.
    Keywords:  3D-printing; cancer vaccine; immunotherapy; lattice microneedle; nanovaccine
    DOI:  https://doi.org/10.1021/acsnano.5c13784
  48. RSC Adv. 2026 Apr 08. 16(21): 19511-19523
    Inducible secretion of LIGHT by engineered probiotics enables localized cytokine therapy and robust antitumor immunity.
    Xinyu Li, Shuaijie Ding, Biao Yang, Yi Wang, Wei Xie.
      Triple-negative breast cancer (TNBC), exemplified by the 4T1 model, exhibits a highly immunosuppressive tumor microenvironment (TME) and strong metastatic potential, resulting in poor responses to current immunotherapies. TNFSF14 (LIGHT) is a potent immunostimulatory cytokine capable of remodeling the TME through the HVEM and LTβR signaling. However, its systemic administration is limited by dose-dependent toxicity. Here, we developed a tumor microenvironment-responsive engineered E. coli system for targeted LIGHT delivery. LIGHT expression was controlled by a lactic acid-inducible promoter and fused with pelB for periplasmic secretion, ensuring selective activation within lactic acid-rich tumor cores. In BALB/c mice bearing 4T1 subcutaneous tumors and experimental lung metastases, intravenously administered bacteria were evaluated for biodistribution, antitumor efficacy, and immune modulation. The engineered strain selectively colonized tumors, achieving strong intratumoral LIGHT expression with minimal systemic exposure. Compared with vector controls, LIGHT-expressing bacteria significantly suppressed primary tumor growth and markedly reduced lung metastatic lesions. Mechanistically, this treatment increased intratumoral CD8+ T-cell infiltration, enhanced dendritic cell maturation, and shifted the TME toward an immune-activated state. Thus, this lactic acid-responsive bacterial platform enables safe, localized cytokine delivery and represents a promising therapeutic strategy for refractory TNBC.
    DOI:  https://doi.org/10.1039/d5ra09644h
  49. J Control Release. 2026 May 21. pii: S0168-3659(26)00446-3. [Epub ahead of print] 115043
    Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering.
    Jianhao Zeng, Tyler Ellis Papp, Awurama Akyianu, Alejandra Bahena, Lanfranco Leo, Faris Halilovic, Hamideh Parhiz.
      Targeted lipid nanoparticles (tLNPs) enable efficient mRNA delivery to T cells, allowing for in situ generation of chimeric antigen receptor (CAR) T cells without ex vivo manipulation. This strategy has shown promising therapeutic efficacy in preclinical studies of cardiac fibrosis, cancer, and autoimmune diseases. While multiple T-cell surface receptors have been targeted across studies for tLNP-mediated in vivo CAR T-cell generation and exhibit diverse efficiencies, their comparative performance and the mechanisms underlying these differences remain unclear. Here, we systematically compared tLNPs with antibody-based moieties targeting T-cell receptors including CD2, CD4, CD5, CD7, CD8, or a CD4 + 8 dual-targeting combination under identical conditions, assessing their mRNA delivery efficiency in human T cells and PBMCs in vitro, and subsequently validating the best performer in vivo in humanized mice. Among all moieties tested, CD7-targeted tLNPs achieved the highest mRNA delivery to T cells and efficiently generated functional aCD20 CAR T cells in vivo. Mechanistic analysis revealed that receptor internalization, rather than the receptor abundance, is the primary determinant of delivery efficiency, a property intrinsic to each receptor and largely independent of antibody clone. These findings provide a rational framework for selecting optimal targeting moiety to enable highly efficient in vivo CAR T-cell engineering.
    Keywords:  CD7; In vivo CAR-T; Receptor internalization; T cells; Targeted lipid nanoparticles (tLNPs); mRNA delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115043
  50. Tissue Cell. 2026 May 09. pii: S0040-8166(26)00280-6. [Epub ahead of print]102 103587
    Mechanistic reprogramming by stem cell-derived extracellular vesicles: From cargo sorting to tissue regeneration.
    Muhammad Faizan Khan, Hina Wajid, Sumreen Begum.
      Stem cell-derived extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as potent bioactive mediators in regenerative medicine owing to their ability to transfer proteins, lipids, and nucleic acids that regulate intercellular communication and cellular homeostasis. This review provides a comprehensive and critical overview of stem cell-derived EVs, encompassing their classification, biogenesis pathways, isolation strategies, and characterization methodologies. Key EV separation techniques, including ultracentrifugation, size-exclusion chromatography, and immunoaffinity capture, are evaluated for efficiency, purity, and translational suitability. In parallel, state-of-the-art characterization approaches such as nanoparticle tracking analysis, electron microscopy, and mass spectrometry are discussed for their roles in defining EVs size distribution, morphology, and molecular cargo. Accumulating evidence highlights the substantial therapeutic potential of stem cell-derived EVs in diverse regenerative applications, including wound healing, cardiovascular repair, bone regeneration, and the treatment of neurological and metabolic disorders. Importantly, their low immunogenicity, enhanced safety profile, and minimal risk of tumorigenesis position EVs as a compelling alternative to conventional stem cell-based therapies. Collectively, this review synthesizes current advances in EV biology and technology, underscoring the promise of stem cell-derived EVs as next-generation, cell-free therapeutic platforms for regenerative medicine.
    Keywords:  Electron microscopy; Exosomes; HIF-α; Lipoprotein; Monoclonal antibodies; Sequencing; Vegf
    DOI:  https://doi.org/10.1016/j.tice.2026.103587
  51. Int J Dent. 2026 ;2026 3514074
    Hypoxia-Mediated Downregulation of Exosomal miR-128-3p Promotes Lymphangiogenesis via VEGF-C in Oral Squamous Cell Carcinoma.
    Tengchao You, Furong Mao, Kesheng Zhang, Xulin Zhang, Xiaohua Hu.
       Background: Cancer cell-derived exosomal microRNAs (miRNAs) are crucial mediators of intercellular communication within the tumor microenvironment, including with lymphatic endothelial cells (LECs). Hypoxia, a key driver of tumor aggressiveness, modulates exosome release and cargo. However, the specific functions of exosomal miRNAs derived from hypoxic oral squamous cell carcinoma (OSCC) cells are not well defined.
    Methods: We employed a two-phase strategy. In the discovery phase, miRNA sequencing was performed on exosomes from hypoxic exosomes and normoxic exosomes (Norm-exos) Tca-8113 cells, and their pro-lymphangiogenic effects on Human LECs (HLECs) were assessed. In the validation phase, using SCC-9 cells, we investigated the functional role of a candidate miRNA, miR-128-3p, through gain-of-function experiments and identified its target.
    Results: Hypoxic OSCC-derived exosomes (Hypo-exos) were internalized by HLECs and significantly enhanced their proliferation, migration, and tube formation. miR-128-3p was markedly downregulated in Hypo-exos. Overexpression of miR-128-3p reversed the pro-lymphangiogenic effects of Hypo-exos and reduced vascular endothelial growth factor (VEGF)-C expression. A dual-luciferase reporter assay confirmed VEGF-C as a direct target of miR-128-3p.
    Conclusion: Hypo-exos promote lymphangiogenesis, partly through the downregulation of exosomal miR-128-3p, which directly targets and inhibits VEGF-C. This novel miR-128-3p/VEGF-C axis presents a potential therapeutic target for mitigating lymphangiogenesis and metastasis in OSCC.
    Keywords:  VEGF-C; exosome; lymphangiogenesis; miR-128-3p; oral squamous cell carcinoma
    DOI:  https://doi.org/10.1155/ijod/3514074
  52. Int J Biol Macromol. 2026 May 18. pii: S0141-8130(26)02523-7. [Epub ahead of print]367 152596
    Functional shell engineering of bioactive wheat-seedling nanovesicles with chitosan derivatives for synergistic metabolic therapy via enhanced oral delivery.
    Tianwei Guo, Xuhai Zhu, Pei Wang, Zhijie Yao, Runqiang Yang, Fang Lu.
      Plant-derived exosome-like vesicles (PDEVs) have emerged as promising oral delivery carriers, yet their application is severely limited by gastrointestinal instability and poor intestinal absorption. To overcome these barriers, we developed a biohybrid nanoplatform by sequentially coating wheat-seedling PDEVs with trimethyl chitosan (TMC) and carboxymethyl chitosan (CMC) via layer-by-layer self-assembly. This engineering strategy confers enhanced physicochemical stability, effectively protecting the payload against gastric degradation while enabling targeted intestinal release. Mechanistically, the multifunctional shell promotes transepithelial transport by enhancing cellular internalization and reversibly modulating epithelial tight junctions. Importantly, this improved delivery enables synergistic immuno-metabolic effects between the loaded α-lipoic acid (ALA) and the carrier's endogenous bioactives (GABA and folic acid). In a metabolic syndrome cell model, the nanoplatform achieved therapeutic efficacy superior to free drug combinations by suppressing pro-inflammatory cytokines and regulating lipid metabolism. Furthermore, in a high-fat diet-induced zebrafish model, the system significantly reversed abdominal lipid accumulation and alleviated systemic oxidative stress. Overall, this work provides a generalizable surface-engineering strategy for stabilizing natural vesicle carriers and supports their application in synergistic oral metabolic therapy.
    Keywords:  Chitosan; Metabolic syndrome; Oral delivery; Plant-derived exosome-like vesicles; Synergistic therapy; Wheat seedlings
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152596
  53. Microb Pathog. 2026 May 18. pii: S0882-4010(26)00295-0. [Epub ahead of print] 108569
    Hydroxychloroquine Inhibits Porcine Epidemic Diarrhea Virus Infection by Targeting Post-Attachment Stages and Virus-Induced Inflammation In Vitro.
    Yu-Wei Zheng, Cai-Yu Chen, Chia-Yu Chang, Chienjin Huang, Hui-Wen Chang, Min-Yuan Chia.
      Porcine epidemic diarrhea virus (PEDV) causes severe enteric disease in swine and represents a substantial economic threat to the global swine industry. Although vaccines are available, effective antiviral strategies against PEDV remain limited. Hydroxychloroquine (HCQ) is a lysosomotropic agent with reported antiviral and immunomodulatory properties; however, its effects on PEDV infection have not been fully elucidated. In this study, we evaluated the antiviral activity of HCQ against PEDV in vitro and examined its effects on distinct stages of the viral life cycle and host inflammatory signaling. HCQ significantly reduced PEDV replication, viral protein expression, and infectious virus production, as demonstrated by RT-qPCR, Western blotting, immunofluorescence analysis, and plaque assays. Time-of-addition experiments revealed that HCQ exerted minimal effects on virus attachment but effectively inhibited viral internalization, replication, and release. Moreover, HCQ markedly suppressed PEDV-induced expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α, and attenuated activation of the nuclear factor kappa B (NF-κB) signaling pathway. Collectively, these findings demonstrate that HCQ exerts dual antiviral and anti-inflammatory effects against PEDV infection in vitro, highlighting its potential as a host-targeted antiviral strategy.
    Keywords:  Hydroxychloroquine (HCQ); Porcine epidemic diarrhea virus (PEDV); pro-inflammatory cytokines
    DOI:  https://doi.org/10.1016/j.micpath.2026.108569
  54. Int J Biol Macromol. 2026 May 15. pii: S0141-8130(26)02479-7. [Epub ahead of print] 152552
    Injectable polysaccharide-based hydrogel delivering Poria cocos extracellular vesicles promotes hair regeneration in androgenetic alopecia via Wnt/β-catenin signaling.
    Huiting Luo, Shang Wang, Hantao Wang, Xinxin Geng, Qinyi Xu, Lingling Ye, Li Yang, Wei Xiang, Jianwei Wang, Chunli Li, Dazhi Ke.
      Androgenetic alopecia (AGA) is characterized by progressive hair follicle miniaturization driven by premature follicle regression. While extracellular vesicles (EVs) are potent bioactive therapeutics, their clinical translation is hindered by the low yields and poor stability of mammalian-derived sources. Herein, we developed an injectable biomacromolecular hydrogel composed of sodium carboxymethylcellulose (CMCNa), sodium alginate (SA), and hyaluronic acid (HA) to deliver plant-derived Poria cocos extracellular vesicles (PCEVs) for the topical treatment of AGA. This polysaccharide matrix was engineered to localize vesicular cargo within the follicular niche, preserve vesicle integrity, and facilitate the sustained release of PCEVs. The hydrogel exhibited favorable rheological properties, injectability, and cytocompatibility for topical application. In a dihydrotestosterone (DHT)-induced AGA mouse model, topical administration of the PCEV-loaded hydrogel significantly accelerated hair regrowth, enhanced follicle density, and restored hair bulb volume and dermal thickness. Transcriptomic profiling revealed that the therapeutic effect was driven by Wnt/β-catenin signaling activation. Specifically, PCEVs treatment led to the upregulation of differentiation markers homeobox C13 (Hoxc13) and forkhead box N1 (Foxn1), hair-shaft keratin Krt31, and desmoglein 4 (Dsg4), along with the downregulation of stem-cell quiescence markers nuclear factor of activated T cells 1 (Nfatc1) and Cd34. Collectively, this delivery platform effectively leverages plant-derived EV cargo to reverse stem-cell quiescence and promote follicular regeneration, offering a scalable and stable translational strategy for hair loss disorders.
    Keywords:  Androgenetic alopecia; Hair follicle differentiation; Plant-derived extracellular vesicle; Polysaccharide hydrogel; Poria cocos; Wnt/β-catenin signaling
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152552
  55. Biochem Pharmacol. 2026 May 15. pii: S0006-2952(26)00391-6. [Epub ahead of print]251(Pt 1): 118058
    Nanoparticle-Based delivery of proteasome inhibitors for glioblastoma Therapy: Strategies to overcome Blood-Brain barrier and therapeutic resistance.
    Md Ataur Rahman, Mahesh Kumar Yadab, Ehsanul Hoque Apu, Meser M Ali.
      Glioblastoma (GBM), the most malignant primary brain tumor, has a poor prognosis despite surgical resection, radiation, and temozolomide-based chemotherapy. GBM's strong infiltrativeness, intratumoral heterogeneity, activation of compensatory survival mechanisms, and the tight blood-brain barrier (BBB) prevent medication delivery to tumor regions, causing therapeutic failure. Dysregulation of the ubiquitin-proteasome system (UPS), which regulates proteostasis, apoptosis, cell cycle progression, and stress responses, contributes to glioblastoma progression and therapeutic resistance. Thus, proteasome inhibitors (PIs) such bortezomib (BTZ), carfilzomib, ixazomib, and marizomib are promising treatments. However, low BBB penetration, systemic toxicity, and drug resistance mechanisms have hampered its GBM clinical usefulness. Nanoparticle-based therapeutic delivery technologies improve drug solubility, pharmacokinetics, and brain tumor targeting to address these issues. Liposomes, polymeric nanoparticles, dendrimers, inorganic nanoparticles, and exosome-derived vesicles can improve PI bioavailability and treatment efficacy in preclinical GBM models. Surface functionalization with targeted ligands, peptides, and antibodies improves BBB transport and tumor uptake. Stimuli-responsive nanocarriers and multi-modal nanoparticle systems allow regulated drug release and combinatorial delivery of chemotherapeutics, genetic materials, and radiosensitizers. To improve glioblastoma clinical outcomes with nanomedicine and proteasome inhibition, we also explore translational difficulties and prospects. This review provides the UPS's biological role in GBM, proteasome inhibitors and their limitations, and nanoparticle-enabled delivery techniques to bypass BBB barriers and treatment resistance.
    Keywords:  Blood-brain barrier; Glioblastoma; Nanomedicine; Nanoparticle drug delivery; Proteasome inhibitors; Targeted therapy
    DOI:  https://doi.org/10.1016/j.bcp.2026.118058
  56. Small. 2026 May 17. e73817
    Tolerogenic Nanovaccine Synergizing Citrullinated Peptide and TSP-1 Plasmid for Antigen-Specific Immunotherapy of Rheumatoid Arthritis.
    Mo Chen, Die Jia, Yinlong Wu, Ke Wang, Xing Zhao, Xing Guo, Shaobing Zhou.
      Rheumatoid arthritis (RA) is a chronic autoimmune disorder driven by systemic inflammation and progressive joint damage. While antigen-specific immune tolerance holds promise as a therapeutic strategy, its clinical translation is hampered by the rapid clearance and unintended immunogenicity associated with conventional antigen delivery. To address these limitations, we developed a tolerogenic nanovaccine (CMLT) that co delivers a multi epitope citrullinated peptide (CitC) and an immunosuppressive thrombospondin-1 (TSP-1) plasmid via a lipid nanoparticle (LNP) platform. By rationally tuning LNP components, we achieved efficient plasmid encapsulation and stable conjugation of CitC, resulting in homogeneous nanoparticles with favorable stability. In a collagen induced arthritis (CIA) mouse model, prophylactic administration of CMLT potently suppressed disease development, significantly mitigating clinical symptoms, reducing histopathological joint damage, and preserving bone architecture. Mechanistically, CMLT fostered an immunosuppressive microenvironment marked by elevated expression of TGF-β1 and TSP-1, expansion of antigen specific regulatory T cells (Tregs), and suppression of autoreactive antibodies and pro inflammatory cytokines. Therapeutic intervention during active arthritis similarly alleviated inflammation and attenuated joint pathology. This synergistic nanovaccine platform provides a targeted and effective approach for re establishing immune homeostasis in RA.
    Keywords:  citrullinated peptide; immune tolerance; nanovaccine; rheumatoid arthritis; thrombospondin‐1
    DOI:  https://doi.org/10.1002/smll.73817
  57. Immunology. 2026 May 20.
    Gastric Cancer-Derived Exosomal MATN3 Favours Immunosuppressive Tumour Microenvironment by Activating Autophagy in an EGFR/ELK1/ATG12 Signalling Dependent Manner.
    Qianwen Zhao, Shanshan Liu, Xin She, Shiyue Ma, Hui Tang, Danli Peng, Haonan Guo.
      Gastric cancer (GC)-derived exosomes (Exos) have been identified to facilitate GC progression by inducing M2 macrophage polarization. This study investigated the biological function of exosomal matrilin-3 (MATN3) in M2 macrophage polarisation during GC development and its underlying mechanism. Exos were isolated from GC cells and then co-cultured with THP-1-derived macrophages. Macrophage polarisation was evaluated by measuring the levels of M1/M2 macrophage markers. Target molecule expression was evaluated by RT-qPCR, Western blotting and immunohistochemical staining. LC3II expression and the co-localisation of MATN3 and epidermal growth factor receptor (EGFR) were determined by immunofluorescent staining. In vivo growth of GC cells was assessed in a xenograft mouse model. Molecular mechanisms were analysed by Co-IP, ChIP, dual-luciferase reporter assay and ubiquitination assay. MATN3 was highly expressed in GC and its high expression was negatively associated with the overall survival and M1 macrophage marker expression of GC patients. The in vitro experiments validated that MATN3 was secreted by GC-Exos, which promoted M2 macrophage polarisation via autophagy activation. In addition, exosomal MATN3 contributed to in vivo growth of GC cells via promoting M2 macrophage infiltration. Mechanistically, MATN3 interacted with EGFR to enhance its protein stability, which activated Ets-like protein-1 (ELK1) and consequently promoted ATG12-mediated autophagy. Activation of the EGFR/ELK1 pathway abolished exosomal MATN3 silencing-mediated inhibitory effect on autophagy and M2 macrophage polarisation. GC-derived exosomal MATN3 exerted an oncogenic role by inducing M2 macrophage polarisation via activation of the EGFR/ELK1/ATG12 axis-mediated autophagy, which provides potential therapeutic targets for GC.
    Keywords:  EGFR/ELK1/ATG12; MATN3; autophagy; exosome; gastric cancer; macrophage polarisation
    DOI:  https://doi.org/10.1111/imm.70144
  58. Vaccine. 2026 May 22. pii: S0264-410X(26)00562-1. [Epub ahead of print]86 128753
    Targeted delivery of the BCG vaccine to dendritic cells improves protective efficacy against Mycobacterium tuberculosis.
    Claudio Counoupas, Annuurun Nisa, Lucy Baker, Rachel Pinto, Nayan Bhattacharyya, Caroline Demangel, Warwick J Britton, James A Triccas.
      Tuberculosis (TB) is the world's deadliest infectious disease, and the current vaccine, Bacillus Calmette-Guérin (BCG), is only partially effective. We hypothesised that BCG interacts sub-optimally with dendritic cells (DCs), key mediators of adaptive immunity. To improve BCG's efficacy, we engineered the vaccine to express a single-chain variable fragment (scFv) targeting the DEC-205 receptor on DCs (BCG:DEC). This modification enhanced BCG interaction with DEC-205-expressing cells, resulting in increased uptake into host cells and cytokine/chemokine secretion. After vaccination of mice, BCG:DEC increased MHC-II expression on vaccine-site myeloid cells, showed enhanced uptake by skin-resident DC subsets and generated higher frequencies of multifunctional, cytokine-secreting CD4+ T cell populations. Compared to BCG alone, BCG:DEC provided improved and sustained protection up to 20 weeks post-challenge against Mycobacterium tuberculosis in mice. Thus, DC-targeted BCG is a promising approach for TB control.
    Keywords:  Bacillus calmette-guérin (BCG); DEC-205 receptor; Dendritic cells; Tuberculosis; Vaccine efficacy
    DOI:  https://doi.org/10.1016/j.vaccine.2026.128753
  59. Clin Sci (Lond). 2026 May 20. pii: CS20258827. [Epub ahead of print]
    Human umbilical cord mesenchymal stromal cells-derived exosomes from MSCs pretreated with inflammatory factors attenuate renal injury of diabetic mice by regulating macrophage polarization.
    Chenhao Li, Yuan Tian, Ye Yuan, Yujun Du, Ziran Xu, Lisha Li.
      Diabetic nephropathy (DN), a major complication of diabetes mellitus (DM), is characterized by severe clinical manifestations, impaired quality of life, and a high risk of progression to end-stage renal disease, underscoring the urgent need for effective therapeutic interventions. Mesenchymal stromal cell-derived exosomes (MSC-Exo) have emerged as promising candidates for mitigating inflammatory injury in DN due to their immunomodulatory properties, and exosomes derived from MSCs pretreated with inflammatory factors such as TNF-α and IFN-γ may possess enhanced therapeutic potential. In this study, exosomes isolated from human umbilical cord mesenchymal stromal cells were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Their therapeutic effects were evaluated in diabetic mice, focusing on renal inflammation and macrophage polarization. Both normal MSC-Exo (Norm-Exo) and TNF-α&IFN-γ-pretreated MSC-Exo (TNF-α&IFN-γ-Exo) effectively ameliorated kidney injury and promoted M2 macrophage polarization, with TNF-α&IFN-γ-Exo showing superior efficacy. High-glucose-stimulated RAW264.7 cells were used to explore the underlying mechanisms, and high-throughput RNA sequencing identified inhibitor of DNA binding 3 (ID3) as a molecule involved in MSC-Exo-regulated macrophage polarization. Loss-of-function experiments confirmed that ID3 knockdown alone recapitulated the effects of exosomes, promoting M2 polarization and suppressing M1 markers. Conversely, ID3 overexpression attenuated exosome efficacy. Mechanistically, ID3 partially mediated exosome-induced inhibition of the NF-κB pathway. The translational relevance of these findings was further validated in PMA-differentiated THP-1 human macrophages. Collectively, these findings demonstrate that MSC-Exo-particularly TNF-α&IFN-γ-Exo-attenuate diabetic renal injury by modulating macrophage polarization through ID3 regulation, highlighting a novel cell-free immunomodulatory approach for DN therapy.
    Keywords:  Diabetic nephropathy; Exosome; Mesenchymal stromal cell; inflammation; macrophage polarization; pretreat
    DOI:  https://doi.org/10.1042/CS20258827
  60. J Sci Food Agric. 2026 May 20.
    Rational engineering of ribitol dehydrogenase for enhanced thermostability and efficient biocatalytic production of allitol.
    Tianwen Shang, Jiangang Yang, Yan Men, Xuegang Luo, Yueming Zhu, Yuanxia Sun.
       BACKGROUND: Allitol is a rare sugar alcohol with potential as a low-calorie sweetener and food ingredient; however, its biocatalytic production from d-allulose is limited by the thermostability and cofactor efficiency of the ribitol dehydrogenases (RDH).
    RESULTS: In this study, the RDH from Klebsiella oxytoca was engineered for enhanced thermostability using consensus-guided mutagenesis targeting non-conserved, non-active-site residues, followed by stepwise combination. The resulting M4 mutant showed markedly improved thermostability, with its melting temperature (Tm) elevated by 19.6 °C relative to the wild type, accompanied by a 10 °C increase in the optimum reaction temperature and a substantially broader pH activity range. Molecular dynamics simulations indicated that the four substitutions clustered at subunit interfaces and reinforced hydrophobic packing, stabilizing the tetrameric assembly and contributing to enhanced thermostability. An enzyme complex combining M4 with formate dehydrogenase (FDH) was constructed to enable efficient cofactor regeneration. This increased the conversion by 28% compared with the free enzyme combination and achieved nearly complete substrate conversion under optimized conditions.
    CONCLUSION: This study significantly improved the thermostability of RDH using consensus-guided interfacial design and constructed a cofactor-regenerating enzyme complex for the efficient biocatalytic production of allitol. © 2026 Society of Chemical Industry.
    Keywords:  allitol; cofactor regeneration; enzyme complex; protein engineering; ribitol dehydrogenase; thermostability
    DOI:  https://doi.org/10.1002/jsfa.70736
  61. Iran J Biotechnol. 2026 Apr;pii: e4063. [Epub ahead of print]24(2):
    Assessment of Diagnostic Efficacy of Engineered ESAT-6 Linear Epitopes Based on IFN-γ Secretion in Tuberculosis.
    Akram Jokar, Maryam Mohammadi-Sichani, Moslem Jafarisani, Keivan Beheshti-Maal, Ali Hosseinzadeh.
       Background: Tuberculosis (TB) remains a major global health burden, with latent and active infections contributing significantly to morbidity and mortality. Effective diagnostic methods, particularly for latent tuberculosis, are essential for improving disease control and prevention.
    Objectives: This study focused on engineering a recombinant ESAT-6 protein to evaluate its impact on IFN-γ secretion in Peripheral blood mononuclear cells (PBMCs), a key indicator of immune response from TB patients.
    Materials and Methods: Following extraction of the ESAT-6 amino acid sequence from gene bank, linear epitopes were predicted and ranked based on immunogenic potential. The engineered cDNA was constructed, cloned, expressed in E. coli, and purified. Protein expression was confirmed via SDS-PAGE and Western blot analysis. PBMCs from tuberculosis patients were then exposed to varying concentrations (5, 10, and 15 μg) of the engineered ESAT-6 protein, with hemagglutinin serving as a control.
    Results: The engineered ESAT-6 protein, comprising 135 amino acids with an approximate molecular weight of 14 kDa, was successfully produced. The gene fragment encoding this protein was 405 bp in length. Exposure to the recombinant protein induced a dose-dependent increase in IFN-γ secretion from PBMCs compared to the control. Recognition of the linear epitopes by immune cells effectively stimulated the production of IFN-γ, highlighting the immunogenic potential of the engineered ESAT-6 protein.
    Conclusions: These findings demonstrate the utility of the engineered ESAT-6 protein in stimulating robust immune responses, suggesting its potential application in diagnostic assays and as a component of next-generation tuberculosis vaccines. Further research optimizing the structure of ESAT-6 could pave the way for improved tools in the fight against tuberculosis.
    Keywords:   ESAT-6; IFN-γ; Mycobacterium; Protein engineering; Tuberculosis
    DOI:  https://doi.org/10.30498/ijb.2026.501943.4063
  62. J Nanobiotechnology. 2026 May 17.
    Combining receptor engineering and intracellular gelation for cell-based antiviral therapy against coxsackievirus B3.
    Tonggong Liu, Wenjuan Liu, Ziyuan Peng, Jie Wen, Shengjie Wu, Xiaona Zhao, Jingzhe Wang, Dayong Gu.
      Viral myocarditis (VMC), caused by pathogens such as coxsackievirus B3 (CVB3), leads to severe cardiac injury and currently lacks specific therapeutic options. Here, we report a biomimetic antiviral strategy based on receptor engineering and intracellular gelation. By combining genetic and protein engineering, we generated a high-affinity Coxsackievirus and adenovirus receptor mutant (Mut-1_CAR) that markedly enhances the binding of host cardiomyocytes to CVB3. Using photochemical crosslinking, these engineered cells were converted into structurally stable, function-retaining gelated cells (PMs). PMs efficiently adsorb and neutralize virus particles, significantly reducing CVB3 plaque formation in vitro. In a murine model of viral myocarditis, PMs demonstrated excellent in vivo safety and biocompatibility while effectively lowering viral load and mitigating myocardial injury. This study establishes a "receptor enhancement + function fixation" approach for non-immune-dependent viral neutralization, providing a conceptual and technical foundation for the development of novel cell-based biomimetic antiviral therapies.
    Keywords:  Coxsackievirus B3; Gelated cells; High-affinity CAR mutant; Receptor engineering
    DOI:  https://doi.org/10.1186/s12951-026-04559-z
  63. J Orthop Surg Res. 2026 May 20.
    Exosome-functionalized alginate/gelatin composite scaffolds: synergistic enhancement of osteogenic differentiation for bone tissue engineering.
    Mohammadali Meskaraf-Asadabadi, Mohammad Rasool Khazaei, Mahsa Amiri, Zeinab Ghesmati, Elham Ghanbari.
      This study investigates the osteogenic potential of exosome (Exo)-loaded alginate/gelatin (OA/Gel) macromolecular composite scaffolds for human adipose-derived stem cells (hASCs). OA/Gel scaffolds were fabricated and crosslinked with EDC, followed by the incorporation of Exo at concentrations of 0.5, 1, 2, and 4 µL. The scaffolds were characterized in terms of morphology, porosity, swelling behavior, mechanical properties, and cell adhesion. Osteogenic differentiation was assessed through alkaline phosphatase activity, Alizarin Red staining, and RT-PCR for Runt-related transcription factor 2, alkaline phosphatase, and bone gamma-carboxyglutamic acid-containing protein expression. Scanning electron microscopy analysis revealed interconnected pores predominantly within the range of 100-200 μm, with OA/Gel scaffolds demonstrating reduced pore size and enhanced mechanical strength compared to single-component scaffolds. The OA/Gel macromolecular scaffold exhibited optimal pore architecture (~ 180 μm), superior cell adhesion and proliferation, and significantly upregulated osteogenic markers at days 7 and 21. These findings suggest that Exo-loaded OA/Gel scaffolds, particularly at a concentration of 2.0 µL Exo, provide a favorable three-dimensional microenvironment for hASC osteogenic differentiation, highlighting their potential as a promising biomaterials for bone tissue engineering applications.
    Keywords:  Alginate; Bone; Exosomes; Gelatin; Stem cell; Tissue engineering
    DOI:  https://doi.org/10.1186/s13018-026-06945-7
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