bims-engexo Biomed News
on Engineered exosomes
Issue of 2026–02–08
sixty-two papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Exosome precision engineering: A comprehensive method for targeted gene and drug delivery.
  2. Exosome-Based Strategies in Hepatocellular Carcinoma: Mechanisms, Immunotherapy, and Clinical Challenges.
  3. A synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis.
  4. Therapeutic potential of exosomes in malignancies: From drug delivery to clinical application.
  5. Exosomal MiR-223-3p from Adipose-Derived Stem Cells Alleviates Hypoxia/Reoxygenation-Induced Ferroptosis of H9c2 Cells by Inhibiting TFRC.
  6. Biomimetic scaffolds with synergistic BMSC targeting and ROS scavenging for mitochondrial protection and effective bone-defect repair.
  7. The potential mechanisms and regulatory roles of exosomal miRNA in neural repair after spinal cord injury.
  8. Exosomes Enhance Diagnosis and Therapy of Ischemic Heart Disease: Insights and Advances.
  9. Functional analysis and identification of miRNAs associated with lipid metabolism from milk-derived exosomes.
  10. Origin dictates function: The dual roles of exosomes derived from diverse origins in the onset and progression of colorectal cancer (Review).
  11. Promotion of angiogenesis by mesenchymal stem cell exosomes: a new frontier in cutaneous wound healing.
  12. Editorial. Engineered neuroglial organoids: the next neurosurgical revolution?
  13. Controlled pyroptosis of engineered macrophages enables biphasic antitumor via the release of oncolytic bacteria and inflammatory signals.
  14. Mesenchymal Stem Cell-derived Exosomes Alleviate Oxidative Stress and Brain Injuries Through Promoting OPA1 Mediated Mitochondrial Fusion After Intracerebral Hemorrhage.
  15. Mesenchymal stem cell exosomes alleviate ischemic myocardial injury by miR-125b-5p/BTG2 pathway.
  16. Exosome-based strategies and immunotherapy for skin cancer: mechanisms, challenges, and future directions.
  17. ROS-responsive diselenide exosomes restores mitophagy to resolve sterile inflammation in liver IRI.
  18. Exo-nanomaterials in cancer immunotherapy: reprogramming the tumor immune microenvironment.
  19. Targeted Extracellular Vesicles Deliver Asiaticoside to Inhibit AURKB/DRP1-Mediated Mitochondrial Fission and Attenuate Hypertrophic Scar Formation.
  20. Injectable Schiff base-engineered hydrogel for spatiotemporal liraglutide delivery orchestrates diabetic periodontitis regression via multimodal microenvironment reprogramming.
  21. Milk-derived exosomes (MDE) for photosensitizer delivery in photodynamic therapy: A review.
  22. The Molecular Mechanisms and Therapeutic Potentials of Engrailed-1 in Fibrotic Scar Formation Post Glaucoma Filtration Surgery.
  23. Treatment of animal models of Alzheimer's disease with extracellular vesicles or exosomes and involvement of microRNAs.
  24. Immune cells in cerebral small vessel disease: Emerging roles and potential targeting therapies.
  25. Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
  26. Ectopic endometrial mesenchymal stem cell-derived exosomal miR-4466 promotes angiogenesis by targeting RUNX1 in adenomyosis.
  27. Tumor-homing exosomes enable targeted delivery of siRNA and isoimperatorin for overcoming BTK inhibitor resistance in DLBCL.
  28. Enhanced surgical tolerance of schistosomiasis-induced fibrotic liver following treatment with Ziziphus plant extract.
  29. An elastase-responsive "plug-and-play" quercetin-loaded engineered extracellular vesicle platform anchored with anti-PRDX1 antibody for severe acute pancreatitis therapy.
  30. Engineered probiotics for inflammatory bowel disease therapy: mechanisms, delivery strategies, and precision medicine.
  31. Polysaccharide Engineered Nanozymes Target Inflammation for Alleviating Colitis-Associated Mental Disorders via Microbiome-Gut-Brain Axis.
  32. Preconditioned umbilical-cord mesenchymal stem-cell exosomes preserve functional hepatocytes in bile duct-ligated rats through alternate miRNA signaling rather than HGF signaling.
  33. Alendronic acid modified PLGA drug delivery system loaded with 17β-Estradiol and vitamin D3 has anti-osteoporotic effect.
  34. Spatiotemporal Synergistic Effects of Injectable Biomaterials With Two Typical 3D Geometries on Macrophage Modulation for Enhanced Tissue Regeneration.
  35. Mismatch type impacts interference and priming activities in the type I-E CRISPR-Cas system.
  36. [miR-488-5p promotes osteogenic and neurogenic differentiation of rat bone marrow mesenchymal stem cells and enhances neuralized bone regeneration].
  37. DISCERN: Dual-Aptamer-Initiated Sensing Circuit via Engineered Nanozyme for Leukemia Stem Cells Phenotyping.
  38. Engineered Acid-Regulating Liposomal Nanovesicles for Synergistic Photodynamic Pyroptosis and Immunotherapy.
  39. Engineered neuroglial organoids as living neural interfaces for restorative neurosurgery.
  40. Liposomes from red betel (Piper crocatum) extract: A new approach in the delivery of anti-inflammatory drugs.
  41. Exosomal HMGB1 Orchestrates NSCLC Progression and Immunosuppressive Macrophage Polarisation Through the TLR4/NF-κB/IL-6/STAT3 Signalling Cascade.
  42. A Pull-Block Metabolic Engineering Strategy for High-Yield and High-Purity Hyoscyamine Production in Atropa belladonna.
  43. Healthy young human plasma-derived exosomes enhance neural stem cell therapy by suppressing pyroptosis via TXNIP/NLRP3 after intracerebral hemorrhage.
  44. Immunotherapy for Type 2 Diabetes: Mechanisms and Therapeutic Advances.
  45. Liver-specific delivery of MDM2 antisense oligonucleotides counteracts diet-induced metabolic-dysfunction-associated steatotic liver diseases.
  46. Programmable iPSC-derived CAR-NK vesicles remodel the immune microenvironment and eradicate tumors.
  47. Parthenolide attenuated the endometriosis-like lesions by activating autophagy and suppressing NLRP3 inflammasome activity.
  48. The First Pig-to-human Liver Xenotransplantation From Genetically Engineered Pig: A Game Changer in Bridging Therapy.
  49. Osteoarthritic knee: Advances in Epidemiology, Emerging Etiopathologies and Adipose-Derived Stem Cells-based Therapies.
  50. Telitacicept versus belimumab in proliferative lupus nephritis.
  51. The natural biological macromolecule sporopollenin capsules in biomedical applications: A systematic review (2015-2025).
  52. Engineering Mixotrophy in the Chemolithoautotrophic Cupriavidus necator through Hydrogenase Induction.
  53. Rosmarinic Acid-Treated Exosomes Modulate TGF-β1/Smad3 Signaling to Alleviate Cardiac Fibrosis in an In Vitro/In Vivo Model.
  54. Engineered mesenchymal stem cells-laden chondroitin sulfate hydrogel promotes diabetic wound healing through ROS scavenging and macrophage polarization.
  55. Large and low-PEG lipid nanoparticles enable efficient dendritic cell targeting for potent mRNA Cancer vaccines.
  56. Antifungal peptides: From modes of action to synergistic and immunologic potential.
  57. Progress in Targeting the Untouchables: Emerging Approaches for Hard-to-Drug Cancer Targets.
  58. Extreme-Environment Adaptive Hydrogel with Vagus Nerve Modulation for Diabetic Wound Healing and Emotion Management.
  59. Assessing target genes for homing suppression gene drive.
  60. Extracellular exosome signature links hypertension and Alzheimer's disease.
  61. Targeted Nanodelivery of WGX50 and Curcumin via Gold Nanoparticles for Alzheimer's Therapy.
  62. Modulation of Clostridioides difficile virulence by metabolites derived from probiotic consortia and genetically edited strains.
  1. Pathol Res Pract. 2026 Jan 26. pii: S0344-0338(26)00020-8. [Epub ahead of print]280 156369
    Exosome precision engineering: A comprehensive method for targeted gene and drug delivery.
    Hailah M Almohaimeed, Hadeel Abdulrahman Waggas, Osama Mohammed Abdulaziz Altowaijri, Jawaher A Abdulhakim, Zuhair M Mohammedsaleh, Amany I Almars, Aniruddha Chatterjee, Bikram Dhara, Daniel Ejim Uti.
      Exosomes are small vesicles which cells use to communicate with one another by way of transporting proteins, lipids and nucleic acids. They are promising vectors that can be applied in the delivery of drugs and genes to locations because of their natural compatibility with the body, stability, and capability to go through biological barriers. Recent advances in the field of exosome & synthetic biology resulted in new engineering strategies expanding their applicability to therapeutic applications. Scientists can target their surfaces with ligands, antibodies, or peptides to enhance accuracy of targeting, and through the development of more sophisticated loading methods- remote loading, stimuli responsive systems- nucleic acids and small molecules can be delivered effectively. Genetically engineered exosomes can deliver CRISPR/Cas9 available in biological therapy to modify immune responses and invent novel cancer-treatment options. However, high-level production, safety of the immune issues and regulatory approval are still challenges that should be overcome. The review explains the newest approaches and the issues that are yet to be resolved and emphasizes the potential that engineered exosomes can offer as versatile platforms to facilitate precision medicine and treatment of diseases.
    Keywords:  Engineered exosomes; Exosomes; Gene therapy; Immunotherapy; Targeted delivery
    DOI:  https://doi.org/10.1016/j.prp.2026.156369
  2. J Gastroenterol Hepatol. 2026 Feb 02.
    Exosome-Based Strategies in Hepatocellular Carcinoma: Mechanisms, Immunotherapy, and Clinical Challenges.
    Husni Farah, Munthar Kadhim-Abosaoda, Hayjaa Mohaisen-Mousa, Renuka Jyothi, Priya Priyadarshini-Nayak, Bethanney Janney-J, Gurjant Singh, Ashish Singh-Chauhan, Manoj Kumar-Mishra.
      Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide, characterized by late diagnosis, limited therapeutic options, and poor prognosis. Conventional systemic therapies such as sorafenib and its successors provide only modest survival benefits and are frequently complicated by toxicity and drug resistance. In recent years, immunotherapy has emerged as a promising avenue, yet its efficacy is often restricted by the profoundly immunosuppressive tumor microenvironment (TME). Within this landscape, exosomes-nanoscale extracellular vesicles secreted by tumor, stromal, and immune cells-have gained increasing attention for their central role in intercellular communication. They influence immune modulation, metabolic reprogramming, and therapeutic resistance, while also serving as potential biomarkers, nanocarriers, and vaccine platforms. Tumor-derived exosomes (TEXs) contribute to immune evasion by suppressing CD8+ T cells, polarizing macrophages toward protumoral phenotypes, and enhancing immune checkpoint resistance. Conversely, engineered exosomes demonstrate significant therapeutic potential by reprogramming TAMs, improving drug delivery, and acting as cancer vaccines. Despite these advances, challenges remain in exosome biogenesis, heterogeneity, large-scale production, and off-target effects, which hinder clinical translation. Furthermore, interactions between exosomes and gut microbiota in modulating hepatic immunity represent an emerging frontier with unexplored therapeutic implications. Continued advances in bioengineering, nanotechnology, and systems biology are expected to refine exosome-based therapies, offering novel, personalized strategies to improve outcomes for HCC patients.
    Keywords:  drug delivery; exosomes; hepatocellular carcinoma; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1111/jgh.70245
  3. Biomaterials. 2026 Feb 02. pii: S0142-9612(26)00048-7. [Epub ahead of print]330 124024
    A synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis.
    Jinwu Wang, Chao Lou, Zhihao Shen, Jin Yang, Hongyi Jiang, Heng Yu, Yu Zhang, Yangbo Li, Hua Chen, Aimin Wu, Zengjie Zhang, Leyi Cai, Wenhao Zheng.
      Osteoarthritis (OA) progression is driven by persistent oxidative stress and ferroptosis, which erode chondrocyte viability and extracellular matrix integrity. Although mesenchymal stem cell-derived exosomes (MSC-EXO) hold regenerative promise, their native cargo lacks the adaptability to withstand such a hostile microenvironment, limiting therapeutic efficacy. Here, we demonstrated a synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis. Firstly, the reverse-adaptation strategy in which OA-like oxidative stress was harnessed to precondition MSCs, thereby identifying miR-142a-3p as a key therapeutic mediator in tert-butyl hydroperoxide (TBHP)-modified exosomes (T-EXO). Subsequently, we engineered MSC-derived exosomes via miR-142a-3p electroporation (EXOmiR-142a-3p) with unique anti-ferroptosis and antioxidative properties. EXOmiR-142a-3p were markedly enriched with miR-142a-3p, which directly targeted the GSK3β/Nrf2/SLC7A11 axis to suppress ferroptosis and reactive oxygen species (ROS) accumulation. Compared to naive EXO, EXOmiR-142a-3p exhibited superior protection against cartilage matrix degradation and significantly slowed OA progression in a murine model. By integrating these engineered exosomes into a biodegradable, cartilage-targeted, and lubricious microsphere platform, we achieved sustained, site-specific delivery that amplified therapeutic durability and efficacy. This platform robustly mitigated extracellular matrix (ECM) degradation, ferroptosis, and oxidative stress in vitro, and conferred significant cartilage protection in a destabilization of medial meniscus (DMM)-induced OA model via efficient, prolonged intra-articular release. Collectively, this innovative approach not only provides potent cartilage protection in preclinical models but also establishes a paradigm for precision, microenvironment-adaptive regenerative therapies for OA and other degenerative diseases.
    Keywords:  Exosomes; Ferroptosis; Hydrogel microspheres; Osteoarthritis; miR-142a-3p
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124024
  4. Pathol Res Pract. 2026 Mar;pii: S0344-0338(26)00032-4. [Epub ahead of print]279 156381
    Therapeutic potential of exosomes in malignancies: From drug delivery to clinical application.
    Roshni Bibi, Arunika Koley, Koustav Sarkar.
       BACKGROUND: Cancer remains one of the most pressing global health challenges, with conventional treatments such as chemotherapy and radiotherapy constrained by modest efficacy and severe long‑term adverse effects. Exosomes-nano‑sized extracellular vesicles (30-150 nm) secreted by diverse cell types-have emerged as promising candidates for cancer diagnosis and therapy due to their inherent biocompatibility, low immunogenicity, and ability to cross biological barriers.
    METHODS: A comprehensive review of recent literature was conducted to summarize advancements in exosome biology, isolation techniques, and engineering strategies relevant to cancer nanomedicine. Particular emphasis was placed on ESCRT (Endosomal Sorting Complex Required for Transport) dependent biogenesis mechanisms, molecular cargo profiling, and applications in targeted drug delivery.
    RESULTS: Tumor‑derived exosomes play multifaceted roles in cancer progression, including modulation of the tumor microenvironment, facilitation of metastasis, and induction of therapeutic resistance. Their molecular cargo-comprising proteins, lipids, and nucleic acids-serves as a dynamic reflection of the physiological or pathological status of the tumor cells. Technological innovations in exosome isolation, surface modification, and therapeutic payload loading have markedly improved targeted delivery and preclinical treatment outcomes. Notably, drug‑loaded exosomes demonstrate the ability to circumvent multidrug resistance.
    CONCLUSION: Exosomes hold substantial promise for precision oncology through enhanced drug delivery and diagnostic applications. However, clinical translation requires standardized manufacturing, comprehensive safety profiling, and scalable production methods to address current limitations. Emerging strategies such as exosome mimetics and AI‑assisted production optimization poised to address these limitations, guiding the development of personalized, efficient, and targeted cancer treatments.
    Keywords:  Cancer therapy; Drug delivery systems; Exosomes; Nanomedicine
    DOI:  https://doi.org/10.1016/j.prp.2026.156381
  5. Int Heart J. 2026 ;67(1): 87-97
    Exosomal MiR-223-3p from Adipose-Derived Stem Cells Alleviates Hypoxia/Reoxygenation-Induced Ferroptosis of H9c2 Cells by Inhibiting TFRC.
    Zhuyuan Liu, Yanru He, Chunshu Hao.
      Myocardial ischemia-reperfusion injury (MI/RI) refers to the deterioration of cardiac function after restoring ischemic myocardium perfusion. Stem cell exosomes have produced unique advantages in treating MI/RI. However, the roles of exosomal microRNA-223-3p (miR-223-3p) from adipose-derived stem cells (ADSCs) on MI/RI are still unclear. This study aimed to investigate the effects of exosomal miR-223-3p from ADSCs on hypoxia/reoxygenation (H/R)-induced H9c2 cell injuries. Our findings indicated that the separated ADSC-derived exosomes (ADSC-Exo) were spherical, with a complete cell membrane, an average diameter of 110 nm, and CD9 and CD63 expression. ADSC-Exo increased the cell viability, proliferation, glutathione (GSH) level, and glutathione peroxidase 4 (GPX4) and miR-223-3p expression and decreased the apoptosis, reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ levels and acyl-CoA synthetase long chain family member 4 (ACSL4) and transferrin receptor (TFRC) expression of H9c2 cells. Overexpressing exosomal miR-223-3p from ADSCs further strengthened the effects of ADSC-Exo on H9c2 cells. Overexpressing TFRC in H9c2 cells effectively reversed the effects of miR-223-3p overexpressed ADSC-Exo on H9c2 cells. In addition, miR-223-3p targeted and negatively regulated TFRC. This study confirmed that exosomal miR-223-3p from ADSCs alleviated H/R-induced ferroptosis of H9c2 cells by inhibiting TFRC, providing a novel target and pathway for the clinical treatment of MI/RI.
    Keywords:  Cardiomyocyte injury; Exosomes; Iron metabolism; MicroRNA; Oxidative stress
    DOI:  https://doi.org/10.1536/ihj.25-398
  6. J Nanobiotechnology. 2026 Feb 03. 24(1): 125
    Biomimetic scaffolds with synergistic BMSC targeting and ROS scavenging for mitochondrial protection and effective bone-defect repair.
    Sheng Yao, Lian Zeng, Huan Wang, Jia Liu, Xiaojian Cao, Zhenguo Xu, Youran Zhang, Sitao He, Bing Ye, Tingfang Sun, Xiaodong Guo.
      The reconstruction of large bone defects remains a significant clinical challenge, primarily owing to the insufficient mitochondrial protection and osteogenic activity of conventional implants. Exosomes (EXOs) derived from mesenchymal stem cells have emerged as promising tools for bone repair. This study reports a mitochondria-targeted therapeutic strategy utilizing EXOs derived from bone marrow mesenchymal stem cells (BMSCs). On MitoQ incorporation, these EXOs (EXO-MitoQ, EM) exhibit the targeted scavenging of mitochondrial reactive oxygen species; moreover, on surface decoration with the nucleic acid aptamer Apt 19 S (EM-Apt), they show the enhanced recruitment and precise delivery of BMSCs. The engineered EXOs show robust BMSC-targeting specificity and mitochondrial protective efficacy. To optimize their regenerative microenvironment and biomechanical properties further, these functionalized EXOs are integrated onto a 3D-printed β-tricalcium phosphate scaffold coated with a small intestinal submucosa (SIS) hydrogel, forming a composite system (TCP/SIS@EM-Apt). In a rat calvarial defect model, this TCP/SIS@EM-Apt scaffold increased the BV/TV by 1.9-fold compared to TCP/SIS, due to the combination of multiple multifunctional therapeutic effects (anti-inflammatory, angiogenic, and osteogenic). The mitochondria-targeting strategy proposed in this study presents a promising solution for the reconstruction of large bone defects and offers a synergistic approach for addressing complex regenerative challenges.
    Keywords:  Biomimetic scaffolds; Bone regeneration; Exosomes; Mitochondrial protection; ROS scavenging; Targeted delivery
    DOI:  https://doi.org/10.1186/s12951-025-04004-7
  7. Front Cell Neurosci. 2025 ;19 1711454
    The potential mechanisms and regulatory roles of exosomal miRNA in neural repair after spinal cord injury.
    Yuanhu Shi, Zhilong Li, Yuanxu Pu, Qinghua Wang, Zhiming Cui, Longju Qi, Yuyu Sun.
      Spinal cord injury (SCI) is a devastating disorder of the central nervous system. It is characterized by primary mechanical damage and secondary pathological cascades. These lead to persistent sensory and motor deficits, substantial socioeconomic burdens, and limited therapeutic efficacy. Exosomes are nanoscale vesicles secreted by various cells that serve as key mediators of intercellular communication by delivering bioactive molecules, particularly microRNAs (miRNAs), which regulate gene expression in target cells. This review explores how exosomal miRNAs contribute to neural repair in SCI. These contributions include inhibiting neuroinflammation via pathways such as NF-κB and TLR4; suppressing neuronal apoptosis through PTEN/PI3K/Akt signaling; promoting axonal regeneration via the ERK1/2/STAT3 and NGF/TrkA pathways, enhancing angiogenesis by targeting SPRED1 and integrin α5, and modulating of the immune microenvironment toward M2 polarization, and multifaceted neuroprotection involving alleviating autophagy and endoplasmic reticulum stress. Drawing on recent preclinical studies from 2024-2025, including those utilizing mesenchymal stem cell-derived exosomes loaded with miRNAs such as miR-124-3p, miR-338-5p, and miR-216a-5p, the review highlights promising innovations, such as bioengineered exosomes and biomaterial integrations. Recent preclinical advancements, such as exosome-based therapies that have shown reduced lesion volumes and improved motor function in rodent models, highlight the potential for translation to clinical applications. Ongoing efforts are anticipated to lead to clinical trials in the near future. Despite challenges in standardization, delivery efficiency, immunogenicity, and long-term safety, exosomal miRNA therapy offers a cell-free, multitargeted approach with strong potential for clinical translation in SCI management.
    Keywords:  axonal regeneration; exosomes; microRNA; neuroinflammation; spinal cord injury
    DOI:  https://doi.org/10.3389/fncel.2025.1711454
  8. J Cardiovasc Transl Res. 2026 Feb 04. 19(1): 12
    Exosomes Enhance Diagnosis and Therapy of Ischemic Heart Disease: Insights and Advances.
    Meng Li, Junping Zhang, Shichao Lv, Yue Zhang, Yiqi Qin.
      Ischemic heart disease is a leading cause of global morbidity and mortality, yet early diagnosis and targeted therapies remain limited. Exosomes, small extracellular vesicles carrying nucleic acids, proteins, and lipids, mediate intercellular communication and show promise for diagnostic and therapeutic use due to their stability, biocompatibility, and targeted delivery. Circulating exosomal profiles reflect myocardial pathology, enabling early detection, risk stratification, and monitoring. Exosomes from mesenchymal stem cells, immune cells, endothelial cells, and other stem cells exert cardioprotective effects. This review summarizes advances in exosome-based diagnostics and therapies and highlights their potential as biomarkers and innovative treatments.
    Keywords:  Diagnosis; Exosomes; Ischemic heart disease; Treatment
    DOI:  https://doi.org/10.1007/s12265-025-10721-z
  9. J Anim Sci Biotechnol. 2026 Feb 04. 17(1): 20
    Functional analysis and identification of miRNAs associated with lipid metabolism from milk-derived exosomes.
    Xin Lu, Tianyu Deng, Yue Liu, Xiaohan Zhang, Xue Bai, Xibi Fang, Runjun Yang.
       BACKGROUND: Exosomes are crucial mediators of intercellular communication. As a key component of milk, milk-derived exosomes are abundant in genetic cargo, particularly microRNAs (miRNAs), indicating their potential role in regulating mammary gland physiology. Therefore, this study aimed to investigate the specificity of miRNAs in milk-derived exosomes and their regulatory roles in lipid synthesis in bovine mammary epithelial cells (BMECs).
    RESULTS: Based on 17,838 DHI records showing a significantly higher milk fat percentage (MFP) in late lactation (4.24% ± 1.07%), 10 high- (5.96% ± 0.26%, HMF) and 10 low-MFP (1.68% ± 0.23%, LMF) cows were selected during this stage for milk-derived exosome isolation and miRNA profiling. Exosomes isolated via differential ultracentrifugation were verified as 50-150 nm vesicles expressing CD9, CD81, and TSG101. miRNA sequencing identified 1,320 differentially expressed miRNAs (496 upregulated and 824 downregulated) between the HMF_EXO and LMF_EXO groups. Uptake assays confirmed that BMECs internalized these exosomes, and qRT-PCR validation showed that miR-423-5p and miR-125b were significantly upregulated and downregulated in HMF_EXO- and LMF_EXO-treated BMECs, respectively. Functionally, exosomal miR-423-5p promoted intracellular lipid accumulation and TG synthesis in BMECs by targeting APOA5, whereas miR-125b inhibited lipolysis and fatty acid oxidation by repressing SLC27A1.
    CONCLUSIONS: This study demonstrates that milk-derived exosomal miRNAs represent a novel mechanism for regulating milk fat synthesis. Specifically, miR-423-5p and miR-125b directly modulated lipid metabolism in BMECs via the miR-423-5p/APOA5 and miR-125b/SLC27A1 pathways. These findings provide new insights into the molecular regulation of milk fat synthesis and highlight the importance of exosome-mediated intercellular communication in the lactating mammary gland.
    Keywords:  Dairy cattle; Lipid metabolism; Milk fat percentage; Milk-derived exosomes; miRNA
    DOI:  https://doi.org/10.1186/s40104-025-01331-5
  10. Oncol Rep. 2026 Apr;pii: 64. [Epub ahead of print]55(4):
    Origin dictates function: The dual roles of exosomes derived from diverse origins in the onset and progression of colorectal cancer (Review).
    Zhao Guo, Haoyan Zhuang, Qingfeng Liu.
      Globally, colorectal cancer (CRC) ranks third in terms of incidence, while it is the second leading cause of cancer‑related mortality. The high incidence and mortality rates of CRC pose a considerable challenge to global human health. Currently, surgical treatment and chemotherapy, which exert unsatisfactory clinical benefits in patients with CRC, are posing major issues in clinical practice, including recurrence, drug resistance and drug toxicity. Therefore, novel treatment approaches for CRC are urgently needed. Emerging evidence has suggested that exosomes carry out a key role in the occurrence and development of CRC, thus attracting considerable attention from researchers. However, exosomes act in a source‑dependent manner as exosomes from different sources can exhibit distinct roles in the onset and progression of CRC. The present review systematically summarizes the molecular mechanisms underlying the effects of exosomes from different sources on promoting or inhibiting CRC. Additionally, the potential of exosomes in the diagnosis and treatment of CRC are also discussed, thus providing a foundation for the future application of exosomes in managing CRC.
    Keywords:  colorectal cancer; dual role; exosome source; exosomes
    DOI:  https://doi.org/10.3892/or.2026.9069
  11. Br Med Bull. 2026 Jan 02. pii: ldag003. [Epub ahead of print]157(1):
    Promotion of angiogenesis by mesenchymal stem cell exosomes: a new frontier in cutaneous wound healing.
    Mohammad Kalhorniagolkar, Ahmad Oryan, Nicola Maffulli.
       INTRODUCTION: Angiogenesis plays a pivotal role in cutaneous wound healing by restoring vascular supply to regenerating tissues. Mesenchymal stem cell-derived exosomes (MSC-exosomes) are emerging as potent acellular mediators of angiogenesis, thanks to their cargo of bioactive molecules and immunomodulatory effects.
    SOURCES OF DATA: This review synthesizes recent findings from in vivo and in vitro studies, including preclinical models of diabetic wounds, ischemic injuries, and burn healing. It draws upon peer-reviewed articles published in biomedical journals, with a focus on the mechanisms and efficacy of MSC-exosomes.
    AREAS OF AGREEMENT: MSC-derived exosomes enhance endothelial cell proliferation, migration, and tube formation. Their ability to activate pro-angiogenic signaling pathways, such as Wnt/β-catenin, AKT/eNOS, and angiopoietin/TIE2, is widely accepted. Additionally, their low immunogenicity, enhanced stability, and potential for bioengineered delivery systems are recognized advantages over other angiogenic therapies.
    AREAS OF CONTROVERSY: Challenges persist regarding the standardization of exosome isolation, characterization, and large-scale production. Debate also exists about their long-term safety and therapeutic consistency across MSC sources.
    GROWING POINTS: Incorporation of MSC-exosomes into hydrogels and scaffolds offers promising controlled delivery systems that enhance angiogenic efficacy. Preconditioning MSCs (e.g. with hypoxia or pharmacological agents) further improves the pro-angiogenic potency of exosomes.
    AREAS TIMELY FOR DEVELOPING RESEARCH: Future efforts should prioritize clinical translation by developing GMP-compliant production protocols, optimizing delivery strategies, and conducting rigorous clinical trials to assess safety, dosing, and therapeutic efficacy across diverse wound types.
    Keywords:  angiogenesis; exosomes; mesenchymal stem cells; signaling pathways; tissue regeneration; wound healing
    DOI:  https://doi.org/10.1093/bmb/ldag003
  12. Neurosurg Focus. 2026 Feb 01. 60(2): E6
    Editorial. Engineered neuroglial organoids: the next neurosurgical revolution?
    Jonathan P Miller.
      
    DOI:  https://doi.org/10.3171/2025.11.FOCUS251042
  13. Cell Rep. 2026 Jan 28. pii: S2211-1247(25)01690-0. [Epub ahead of print]45(2): 116918
    Controlled pyroptosis of engineered macrophages enables biphasic antitumor via the release of oncolytic bacteria and inflammatory signals.
    Leyang Wu, Chenyang Li, Liyuan Qiao, Lin Li, Shuhui Zhang, Bohao Wang, Ying Sun, Jiahui Qiu, Baolian Huang, Xinyue Qiao, Zengzheng Du, Xiaoyao Chang, Hongqin Zhuang, Tao Zhang, Yanlong Jia, Tianyun Wang, Wenjie Ren, Xiaowei Luan, Yujun Song, Heng Liu, Yun Xu, Zichun Hua.
      Engineered macrophage-based therapies offer promising potential for cancer treatment but are limited by slow, uncontrolled drug release and the risk of macrophage reprogramming into tumor-promoting phenotypes. Here, we developed a thermally induced macrophage autolysis release system, the macrophage-microbe encapsulation bomb (MME-Bomb), which combines engineered macrophages loaded with indocyanine green-encapsulated nanoparticles and an antitumor attenuated Salmonella typhimurium strain. Photothermal therapy is used to induce controlled pyroptosis and rupture of the encapsulated macrophages within the tumor microenvironment, releasing intracellular bacteria to stimulate prolonged antitumor immunity. By integrating light-responsive biomodulation, our approach enables site-specific activation of engineered cells, enhancing the rapid delivery of therapeutic agents and maximizing the synergy between macrophage-based and bacterial therapies. In preclinical cancer models, the MME-Bomb significantly reduced the tumor burden and improved survival outcomes, both alone and in combination with checkpoint inhibitors. This innovative strategy offers a versatile and precise framework for advancing cancer immunotherapies.
    Keywords:  CP: cancer; CP: microbiology; cell therapy; microbial therapeutics; multiple immunotherapy; pyroptosis; thermal initiation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116918
  14. Mol Neurobiol. 2026 Feb 07. 63(1): 426
    Mesenchymal Stem Cell-derived Exosomes Alleviate Oxidative Stress and Brain Injuries Through Promoting OPA1 Mediated Mitochondrial Fusion After Intracerebral Hemorrhage.
    Yanni Xu, Yong Du, Qing Hu, Ping Wang, Yaning Cai, Gaoyang Zhou, Haixiao Liu, Wei Guo.
      Oxidative stress (OS) is a hallmark of secondary brain damage after intracerebral hemorrhage (ICH), contributing to the progression of neurological damage and poor clinical outcomes. While mesenchymal stem cell-derived exosomes (MSC-Exo) demonstrate antioxidative potential, the specific mechanisms underlying their protective effects, particularly concerning mitochondrial dynamics, remain unclear. This study identifies OPA1-mediated mitochondrial fusion as a novel mechanism through which MSC-Exo alleviates oxidative stress and brain injury after ICH. In vivo fluorescence imaging and immunofluorescence assay revealed that intravenously injected MSC-Exo could be effectively internalized by neuronal cells in ICH mice. MRI assay indicated that although MSC-Exo had little effect on the volume of hematoma, it significantly relieved brain edema and improved the neurological outcomes. MSC-Exo effectively reduced oxidative stress and neuronal apoptosis in the peri-hematoma tissues. Notably, both in vivo and in vitro studies showed that MSC-Exo significantly alleviated mitochondrial morphological damage following ICH. MSC-Exo substantially reversed the downregulation of OPA1 after ICH but showed no significant impact on other proteins associated with mitochondrial dynamics. Neuron-specific knockout of OPA1 (Opa1cko) aggravated the impairment of mitochondrial morphology, the accumulation of superoxide production, and the deficits of mitochondrial respiratory capacities following ICH. Moreover, MSC-Exo failed to restore mitochondrial morphology and functionality, alleviate oxidative stress-induced damage, enhance neuronal viability, and facilitate functional recovery subsequent to ICH in Opa1cko mice models.
    Keywords:  Exosome; Intracerebral hemorrhage; Mesenchymal stem cells; Mitochondrial fusion; OPA1; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-026-05703-4
  15. Mol Cell Biochem. 2026 Feb 05.
    Mesenchymal stem cell exosomes alleviate ischemic myocardial injury by miR-125b-5p/BTG2 pathway.
    Lijun Luo, Lieyou Li, Shuyun Wu, Xinjie Zeng, Lin Fan.
      MicroRNAs mediate the protective effects of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) against myocardial injury. This study aimed to elucidate the specific role of exosomal miR-125b-5p in ischemic myocardial injury, focusing on its regulatory interaction with B-cell translocation gene 2 (BTG2). Murine BMSCs were transfected with miR-125b-5p inhibitor or negative-control (NC) oligonucleotides and then used to generate miR-125b-5p-knockdown (miR-125b-5pKD)-Exos or NC-Exos under hypoxic condition. In vivo, myocardial infarction (MI) was induced by LAD ligation, followed by intramyocardial injection with 50 μl of PBS, or containing 200 μg of NC-Exos, or miR-125b-5pKD-Exos. In vitro, HL-1 cells were treated with NC-Exos or miR-125b-5pKD-Exos at a final concentration of 50 μg/ml under hypoxia/serum-deprived (HSD) condition. Cell apoptosis, inflammation, fibrosis, cardiac function and BTG2 expression were assessed. Exosomes uptake was detected by fluorescence microscopy after exosomes labeled with DiD dye were injected into ischemic myocardium or co-cultured with HL-1 cells under HSD condition. Dual-luciferase reporter assay was applied to validate miR-125b-5p/BTG2 interaction. When compared with group MI, treatment with NC-Exos significantly alleviated the inflammatory response (inflammation score: 1.70 ± 0.37 vs. 3.47 ± 0.22, P < 0.01), inhibited cardiac fibrosis (fibrotic area ratio: 15.98% ± 2.79% vs. 31.55% ± 3.54%, P < 0.01), and improved cardiac function (ejection fraction: 49.48% ± 6.43% vs. 29.35% ± 5.79%, P < 0.01 and fractional shortening: 30.88% ± 3.70% vs. 16.15 ± 2.72%, P < 0.01). NC-Exos reduced the cell apoptosis by 41.5% in vivo (18.00% ± 3.74% vs. 30.75% ± 3.86%, P < 0.01) when compared with group MI and by 52.2% in vitro (10.48% ± 1.80% vs. 21.93% ± 1.76%, P < 0.001) when compared with group HSD. Treatment with NC-Exos also resulted in remarkable down-regulation of BTG2 expression. The knockdown of miR-125b-5p weakened these protective effects of NC-Exos. The effective uptake of DiD-labeled exosomes by ischemic myocardium and HL-1 cells were confirmed by fluorescence microscopy. Dual-luciferase reporter assay further confirmed that BTG2 is the target of miR-125b-5p. BMSC-derived exosomes confer cardioprotection, at least in part, by transferring miR-125b-5p into cardiomyocytes to target BTG2.
    Keywords:  BTG2; Cardioprotection; Exosomes; Myocardial injury; miR-125b-5p
    DOI:  https://doi.org/10.1007/s11010-026-05494-1
  16. Med Oncol. 2026 Feb 05. 43(3): 133
    Exosome-based strategies and immunotherapy for skin cancer: mechanisms, challenges, and future directions.
    Hafez Karimi, Nima Seifollahi, Parnian Yavari, Maryam Pourrostam, Saeideh Nourbakhsh, Shima Rahmati, Gelavizh Rostaminasab.
      Skin cancer continues to be among the top malignancies diagnosed around the world, with rising incidence through the years. The cause of most deaths is the metastatic progression, which commonly limits the success of the treatments available. The commonly used methods of surgery, radiotherapy, and immunotherapy, photodynamic and conventional chemotherapy have improved the patient survival rates tremendously. However, the systemic toxicities and therapeutic resistance limit therapeutic efficacy of these treatments. Hence, developing targeted solutions is essential that tackle these concerns directly. Targeted exosomes as extracellular vesicles (EVs) are unique biological nanocarriers for the direct cell delivery of chemo, nucleic acids, and immune modifiers to tumor cells. The purpose of this review is to survey the literature and examine current exosome research in cancer has to offer, especially in relation to improving focused drug delivery, immune modification, tumor microenvironment (TME) alteration, and skin cancer immunotherapy. We describe evidence from preclinical and developing clinical studies showing the exosome-mediated delivery systems improve the bioavailability of a drug. This occurs through its specificity for tumors, mitigate the systemic toxicity of the drug, and neutralize the mechanisms of immune- and chemotherapy resistance. These new approaches to therapy represent a significant advancement in dermatologic oncology and are likely to improve prognosis and patients' quality of life.
    Keywords:  Exosomes; Immunotherapy; Nano-drug delivery; Regenerative medicine; Skin cancer
    DOI:  https://doi.org/10.1007/s12032-026-03237-2
  17. Eur J Pharm Sci. 2026 Feb 02. pii: S0928-0987(26)00031-X. [Epub ahead of print] 107457
    ROS-responsive diselenide exosomes restores mitophagy to resolve sterile inflammation in liver IRI.
    Tao Zhou, Zhiwei Jiang, Qingluan Hu, Siqi Qiu, Junda Gao, Jianjun Zhang, Feng Xue, Lin Lu, Ling Chang.
      Liver ischemia-reperfusion injury (IRI) drives graft dysfunction and postsurgical morbidity. We show that hepatocellular MST1 is markedly upregulated in IRI and exacerbates damage by blocking PINK1-dependent mitophagy. Defective mitochondrial clearance causes mtDNA leakage, which activates macrophage cGAS-STING signaling and fuels inflammatory injury. Curcumin inhibits this MST1-PINK1 axis, restoring mitophagy and limiting mtDNA release. To translate these insights, we engineered Curcumin@EV@Se-stem-cell-derived extracellular vesicles surface-modified with diselenide-PEG for ROS-responsive, "stealth" delivery. In oxygen-glucose deprivation/reoxygenation models, Curcumin@EV@Se improved hepatocyte viability, preserved mitochondrial potential, reduced ROS and inflammatory cytokines, and promoted reparative/angiogenic programs. In a murine hepatic IRI model, systemic Curcumin@EV@Se decreased necrosis and TUNEL positivity and improved serum transaminases and histology, indicating enhanced liver function and regeneration. These data identify MST1-mediated mitophagy blockade with secondary cGAS-STING activation as a central pathogenic axis in IRI and present Curcumin@EV@Se as a mechanism-guided therapy that restores mitochondrial quality control and dampens innate immune activation, with translational promise for liver transplantation and acute hepatic injury.
    Keywords:  curcumin; stem cells; vesicle
    DOI:  https://doi.org/10.1016/j.ejps.2026.107457
  18. Front Immunol. 2025 ;16 1764525
    Exo-nanomaterials in cancer immunotherapy: reprogramming the tumor immune microenvironment.
    WeiJian Fang, EnDuo Qiu, Rui Liu, ShanLin Wang, TianFu Wang, YuMing Wang.
      Immunotherapies such as checkpoint blockade, adoptive cell transfer and vaccines can induce durable responses, yet most solid tumors remain refractory because the tumor immune microenvironment (TIME) is both immunosuppressive and physically difficult to access. In parallel, extracellular vesicles (EVs) and synthetic nanomaterials have emerged as complementary immune messengers and programmable carriers. Exo-nanomaterials, hybrids that fuse EV membranes with synthetic cores, aim to unite EV biocompatibility and trafficking with the loading capacity, modularity and stimulus-responsiveness of engineered nanomaterials. Here, we summarize how exosomes shape the TIME by distributing checkpoint ligands, reprogramming myeloid cells and modulating antigen presentation, and how nanomaterials are engineered to improve tumor-localized delivery of innate agonists and vaccine cargos. We then outline major construction routes (coating, loading and mimetic fabrication) and design modules that enable cold-to-hot conversion, sensitization to checkpoint blockade, and delivery of neoantigen and nucleic-acid vaccines. Finally, we discuss key translational challenges, including standardization, mechanism deconvolution, scalable manufacturing and safety, and propose immune-by-design principles to guide reproducible, mechanism-grounded development toward durable immunotherapy in solid tumors.
    Keywords:  exosomes; extracellular vesicles; nanomaterials; solid tumors; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2025.1764525
  19. Adv Sci (Weinh). 2026 Feb 04. e17108
    Targeted Extracellular Vesicles Deliver Asiaticoside to Inhibit AURKB/DRP1-Mediated Mitochondrial Fission and Attenuate Hypertrophic Scar Formation.
    Luyu Li, Chenli Si, Xue Wang, Xiaojin Wu, Ying Shang, Shengfang Ge, Yong Wang, Yong Zuo, Zhen Zhang.
      Hypertrophic scars (HS) are fibroproliferative lesions arising from aberrant wound healing, their high incidence is countered by a lack of effective interventions owing to an incomplete understanding of pathogenesis. Here, we identify dysregulated mitochondrial dynamics as a key driver of HS and develop a new targeted therapy. Specifically, excessive mitochondrial fission was observed in macrophages derived from both human and murine HS tissues. In vitro and in vivo experiments revealed that this imbalance is governed by AURKB-mediated phosphorylation of DRP1 at Ser616 site. Through machine-learning coupled with biological validation, we identified the natural small-molecule Asiaticoside (AS) as a potent AURKB inhibitor. However, AS has limited targeting accuracy and poor bioavailability. To overcome these challenges, we developed cRGD-decorated extracellular vesicles (EVs) loaded with AS (AS@cRGD-EVs), enabling targeted delivery of AS to macrophages within wound tissue. In vitro and in vivo studies showed that AS@cRGD-EVs effectively restrained macrophage mitochondrial fission, rebalanced the inflammatory milieu, and conferred significant anti-scarring efficacy in murine HS models. This work establishes mitochondrial dynamics as a therapeutic axis for HS and delivers a targeted nanotherapeutic ready for translational evaluation.
    Keywords:  engineered EVs; hypertrophic scars; machine‐learning; mitochondrial fission; target delivery
    DOI:  https://doi.org/10.1002/advs.202517108
  20. J Control Release. 2026 Feb 04. pii: S0168-3659(26)00089-1. [Epub ahead of print] 114688
    Injectable Schiff base-engineered hydrogel for spatiotemporal liraglutide delivery orchestrates diabetic periodontitis regression via multimodal microenvironment reprogramming.
    Jiamin Li, Rongrong Li, Yan Zhou, Shengping Zheng, Jingjing Xu, Jingli Zhu, Yunqing Pang, Jing Wang.
      The treatment of diabetic periodontitis is significantly challenged by a pathological microenvironment characterized by hyperglycemia, proinflammatory cytokine storm, and excessive reactive oxygen species (ROS), with current therapeutic strategies offering limited efficacy and susceptibility to antibiotic resistance. Although liraglutide (LIRA) possesses multifaceted therapeutic potential, including glycemic control, anti-inflammation, antioxidation, and osteoprotection, its systemic administration fails to achieve effective local concentrations within periodontal tissues. To address this, we engineered an injectable carboxymethyl chitosan-oxidized dextran hydrogel (LIRA@CMCS-OD) via dynamic Schiff base bonds for localized LIRA delivery. This hydrogel exhibited excellent injectability, tissue adhesion, biocompatibility, and pH-responsive drug release kinetics. In vitro studies demonstrated that LIRA@CMCS-OD inhibited Porphyromonas gingivalis growth, effectively scavenged intracellular ROS in human periodontal ligament cells (hPDLCs), and robustly promoted hPDLCs osteogenic differentiation. In a diabetic periodontitis rat model, local application of LIRA@CMCS-OD significantly ameliorated gingival inflammation and tooth mobility, enhanced alveolar bone regeneration, and demonstrated favorable biosafety. By enabling sustained local drug release and orchestrating a synergistic "antibacterial action-antioxidation- osteogenic protection" mechanism, this LIRA-loaded injectable hydrogel presents a potent and safe therapeutic strategy for diabetic periodontitis.
    Keywords:  Antibacterial; Carboxymethyl chitosan; Diabetic periodontitis; Osteogenesis; Oxidized dextran; ROS scavenging
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114688
  21. Photodiagnosis Photodyn Ther. 2026 Jan 29. pii: S1572-1000(26)00037-2. [Epub ahead of print] 105370
    Milk-derived exosomes (MDE) for photosensitizer delivery in photodynamic therapy: A review.
    Kave Moloudi, Nkune Williams Nkune, Heidi Abrahamse, Blassan P George.
      Photodynamic therapy (PDT) is a novel light-based modality that relies on photoactivatable photosensitizers (PSs) to generate cytotoxic reactive oxygen species (ROS), but its clinical prospects are impeded by issues related to poor tumour specificity, penetration and off-target phototoxicity. Milk-derived exosomes (MDE), naturally occurring extracellular vesicles (30-150 nm in diameter) with excellent biocompatibility and low immunogenicity, have recently emerged as promising vehicles in drug delivery. MDE enhance intercellular communication by transporting proteins, lipids, and nucleic acids between cells. They have gained significant attention in recent years for their potential use in drug delivery, particularly for hydrophobic PSs, gene and protein delivery. MDE are of particular interest due to their abundance, ease of isolation, and biocompatibility. Herein we reviewed recent developments in MDE-mediated PDT, with a focus on three key areas: isolation and loading techniques, stimuli-responsive release and targeting such as pH-sensitive linkers or surface-anchored ligands (e.g., folic acid), therapeutic applications and in vivo efficacy. Several lines of evidence showed that MDE loaded with PSs significantly enhance tumour uptake and cause severe regression in in vivo tumour models of glioblastoma and oral cancer, following systemic or oral administration. Overall findings from this review suggest that clinical translation depends on addressing key challenges related to scalable purification, reproducible drug loading and thorough safety profile screening. Therefore, it is essential for researchers to actively standardize manufacturing processes, conduct thorough in vivo validation, and investigate combination therapies with modalities for enhanced therapeutic efficacy.
    Keywords:  Milk-derived exosomes; drug delivery; photodynamic therapy; targeted therapy
    DOI:  https://doi.org/10.1016/j.pdpdt.2026.105370
  22. Invest Ophthalmol Vis Sci. 2026 Feb 02. 67(2): 18
    The Molecular Mechanisms and Therapeutic Potentials of Engrailed-1 in Fibrotic Scar Formation Post Glaucoma Filtration Surgery.
    Yi Lin, Wangdu Luo, Xiaomin Zhu, Julong Yu, Xiangji Li, Lin Xie.
       Purpose: Conjunctival scarring is a major cause of glaucoma filtration surgery (GFS) failure, necessitating effective antifibrotic strategies. This study investigated the role of engrailed-1 (EN1) in conjunctival fibrosis and evaluated the therapeutic potential of EN1-targeted biomaterials for antiscarring in post-GFS patients.
    Methods: Fibrotic models were developed using TGF-β2-induced human Tenon fibroblasts (HTFs) and a rat GFS model. EN1 was identified as a key therapeutic target using RNA interference, transcriptome sequencing, chromatin immunoprecipitation-qPCR, and dual-luciferase assays. Exosomes (Exos) loaded with EN1 small interfering RNA were encapsulated in a GelMA hydrogel to form the Gel-Exo-siEN1 composite material.
    Results: EN1 expression was significantly elevated in TGF-β2-stimulated HTFs and conjunctival scar tissue post GFS. Inhibition of EN1 reduced TGF-β2-induced proliferation and migration in HTFs and decreased fibrosis-related gene expression. These effects may be mediated through the Yes-related protein/transcriptional co-activator PDZ-binding motif and SMAD3 pathways. Assays confirmed that EN1 inhibition suppressed proliferation and migration and downregulated fibrosis markers like fibronectin, collagen I, and α-smooth muscle actin. Western blot analysis showed increased Yes-related protein/transcriptional co-activator PDZ-binding motif expression after TGF-β2 induction, which was reduced by verteporfin. Chromatin immunoprecipitation-PCR confirmed that SMAD3 binds to the EN1 promoter, regulating its expression. Exo analysis showed Exo-siEN1 maintained stability and effectively delivered siEN1, leading to significant EN1 knockdown and reduced fibrosis in rat Tenon's fibroblasts. Gel-Exo-siEN1 treatment significantly increased functional bleb area, reduced IOP, and decreased collagen deposition and inflammatory cell infiltration in the conjunctiva after GFS.
    Conclusions: Gel-Exo-siEN1 is a promising strategy for preventing postsurgical scarring and improving the outcomes of glaucoma surgery.
    DOI:  https://doi.org/10.1167/iovs.67.2.18
  23. Neural Regen Res. 2026 Jan 27.
    Treatment of animal models of Alzheimer's disease with extracellular vesicles or exosomes and involvement of microRNAs.
    Bridget Martinez, Philip V Peplow.
       ABSTRACT: Alzheimer's disease is a complex and devastating neurodegenerative disorder that accounts for roughly 80% of all dementia cases. It is primarily marked by the accumulation of senile amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. These pathological features are accompanied by chronic neuroinflammation and glial cell dysfunction, which collectively contribute to the progressive loss of synapses and neurons. As a result, individuals with Alzheimer's disease experience gradual memory loss and cognitive decline. Currently, the global patient population is nearing 50 million, a number expected to increase dramatically over the coming decades. Conventional treatments focus on symptom management through acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, and the N-methyl-D-aspartate receptor antagonist memantine. However, the past few years have seen the approval of newer agents such as sodium oligomannate, aducanumab, and lecanemab, which show some promise in slowing disease progression. Unfortunately, most patients are not diagnosed until moderate or advanced stages when irreversible brain damage has occurred. This highlights an urgent need for early diagnosis and biomarkers together with therapeutic strategies aimed at early-stage intervention and identifying novel drug targets that address prodromal and established forms of the disease. This article is a literature review of extracellular vesicles/exosomes treatment in animal models of Alzheimer's disease involving microRNAs. In the in vivo animal studies of Alzheimer's disease reviewed, extracellular vesicles and exosomes from various sources improved memory and cognitive decline, lowered inflammation and amyloid deposition, and increased neuron survival in the brain. Loading extracellular vesicles and exosomes with microRNA mimics (e.g., miR-22, -29b, -124, -132, -138-5p, -342-5p, -711, and -7670-3p) or antagomirs (e.g., miR-206-antagomir) improved outcomes in animal models of Alzheimer's disease. Supporting results were found in the in vitro cell studies reviewed.
    Keywords:  Alzheimer’s disease; animal models; exosomes; extracellular vesicles; microRNAs; treatment outcomes
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01116
  24. Neural Regen Res. 2026 Jan 27.
    Immune cells in cerebral small vessel disease: Emerging roles and potential targeting therapies.
    Yating Zhan, Yiqin Wang, Meiling Bai, Juan Feng, Jiayi Wei, Jue Wang.
       ABSTRACT: Cerebral small vessel disease is an age-related condition that severely affects the quality of life of older adults; however, there are currently no definitive treatments or preventive measures. Cells from both the peripheral and central immune systems significantly impact the development of cerebral small vessel disease. By analyzing the effects of different immune cells on brain dysfunction associated with this disease, we aim to explore the various mechanisms through which autoimmune and acquired immune cells in peripheral circulation and the central nervous system contribute to disease development. Additionally, we seek to identify potential therapeutic modalities targeting these immune cells. In innate immunity, treatment targeting different monocyte loci includes four main modalities: cytokines (CSF1R, MIF, P2X7, CX3CR1, and CCL2), signaling pathways (DAP12/TREM, PI3K/AKT, and Wnt/β-catenin), tissue engineering (mitochondrial transplantation and exosomes), and traditional Chinese medicines. Treatment targeting different dendritic cell loci encompasses two modalities: signaling pathway (cGAS/STING/NF-κB) and tissue engineering (tolerogenic dendritic cells and engineered probiotics). For natural killer cells, treatment targeting different loci includes two modalities: tissue engineering (natural killer cell-based immunotherapies) and traditional Chinese medicines (Tongxinluo capsule). In adaptive immunity, treatment targeting different T cell loci includes four modalities: cytokines (S1PR and RXR), signaling pathway (Nrf2/GPX4 and Notch-ITGB1), tissue engineering (elimination of senescent T cells, monoclonal antibodies targeting amyloid-beta protofibrils, nanovaccines, and nanomedicines), and traditional Chinese medicines (traditional herbal remedies and microneedle therapy). Treatment targeting different B cell loci includes three modalities: monoclonal antibodies (targeting CD49d and CD20), purine glycoside analogs (Cladribine), and plasma exchange. This review explores the relationship between nerve regeneration, immune cells, and cerebral small vessel disease. The disease is characterized by the crucial role played by signaling and interactions between immune cells and components of the neurovascular unit, which is a functional complex composed of neurons, glial cells, and microvessels that regulate inflammatory responses and tissue repair. The central nervous system lacks intrinsic regenerative capacity, and currently, there is no effective method to fully restore its function. The primary focus of current research is on utilizing tissue engineering and regenerative medicine to create environments that facilitate cell proliferation and tissue regeneration. Hydrogels, induced pluripotent stem cells, exosomes, regulatory T cell transplants, and gene modification are key areas of focus in neural regeneration research. In the future, immune rejuvenation and other emerging therapies may offer potential treatment strategies for cerebral small vessel disease. This review analyzes the functions of various immune cells in cerebral small vessel disease, explores the relationship between nerve regeneration and these immune cells, and discusses potential therapeutic avenues that target immune cells for future treatments and neural regeneration related to cerebral small vessel disease.
    Keywords:  blood–brain barrier; central nervous system; cerebral small vessel disease; immunization; immunotherapy; neural regeneration; neurodegenerative disorders; neuroinflammation; pathogenesis
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00858
  25. Immunity. 2026 Jan 30. pii: S1074-7613(26)00038-5. [Epub ahead of print]
    Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
    Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B Schroer, Daniel J Richard, Gita C Abhiraman, Andy P Tsai, Eric D Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y Zhou, Matthew T Buckley, Karen E Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A Saxton, Ricardo A Fernandes, Saul A Villeda, K Christopher Garcia, Anne Brunet.
      The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.
    Keywords:  T cells; brain aging; checkpoint inhibitors; engineered proteins; inflammation; interleukin-10; microglia; neuro-immune interactions; neurogenesis; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.016
  26. Biochem Biophys Rep. 2026 Mar;45 102457
    Ectopic endometrial mesenchymal stem cell-derived exosomal miR-4466 promotes angiogenesis by targeting RUNX1 in adenomyosis.
    Jindan Wang, Yongyan Ni, Jiali Sun, Yingying Qiu, Xinjun Wei, Bei Wang, Meihua Huang, Zhenli Li, Tao Gui.
       Background: Abnormal angiogenesis plays vital role in the pathogenesis of adenomyosis (AM). Emerging evidence suggests that exosomes derived from endometrial cells can accelerate the progression of AM. In this study, we aim to investigate the pro-angiogenic role and potential mechanisms of ectopic endometrial mesenchymal stem cells (eMSCs)-derived exosomes (Ec-exo).
    Methods: MicroRNA sequencing was conducted to identify differentially expressed miRNAs (DE-miRNAs) in exosomes derived from normal eMSCs (N-exo) and Ec-exo. Candidate miRNAs were selected using quantitative real-time polymerase chain reaction (qRT-PCR). The effects of miR-4466 on human umbilical vein endothelial cells (HUVECs) proliferation, invasion/migration, and tube formation were analysed in vitro. The target gene of miR-4466 was predicted via bioinformatics analysis and validated by qRT-PCR, western blotting, luciferase assays, and rescue experiments.
    Results: We identified 81 up-regulated and 92 down-regulated miRNAs between N-exo and Ec-exo. Among these DE-miRNAs, miR-4466 was the most significantly up-regulated. The internalisation assay demonstrated that exosomal miR-4466 can be internalised by HUVECs. Overexpression or inhibition of miR-4466 significantly promoted or inhibited HUVEC proliferation, invasion/migration, and tube formation. Bioinformatics predictions and luciferase assays revealed that runt-related transcription factor 1 (RUNX1) is a direct target of miR-4466. Moreover, rescue experiments confirmed that RUNX1 overexpression reversed the pro-angiogenic effect of miR-4466 by inhibiting vascular endothelial growth factor A (VEGFA) expression.
    Conclusions: Our study demonstrates that exosomal miR-4466 derived from ectopic eMSCs promotes angiogenesis by targeting the RUNX1/VEGFA axis in AM. These findings may offer new insights into therapeutic targets and treatment strategies for the anti-angiogenic treatment of AM.
    Keywords:  Adenomyosis; Angiogenesis; Exosomes; RUNX1; eMSCs; miR-4466
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102457
  27. Mater Today Bio. 2025 Dec;35 102267
    Tumor-homing exosomes enable targeted delivery of siRNA and isoimperatorin for overcoming BTK inhibitor resistance in DLBCL.
    Ruowen Sun, Yanchao Yang, Bin Zhang, Jiayuan Chen, Ye Wang, Zehui Jiang, Linlin Zhang, Milad Ashrafizadeh, Gautam Sethi, Jing Shen, Zuofei Chi.
      Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, but over one-third of patients relapse or develop refractory disease after first-line therapy. Novel therapeutic strategies are required to address persistent unmet clinical needs for DLBCL. This study aimed to develop an exosome-based drug delivery system for the targeted combination therapy of siRNA against Bruton's tyrosine kinase (BTK, an established therapeutic target in B cell lymphomas) and isoimperatorin (ISOIM, an active natural furanocoumarin showing anti-tumor effects) in DLBCL. Tumor exosomes were isolated as the delivery carrier. ISOIM/siBTK@Exosome was prepared by encapsulating ISOIM and si-BTK into exosome using electroporation. Cellular uptake, immune escape, targeted delivery efficiency, anti-lymphoma activity and biosafety of ISOIM/siBTK@Exosome were evaluated in two DLBCL cell lines and in tumor-bearing mice. ISOIM/siBTK@Exosome displayed significant anti-lymphoma activity compared to ISOIM@Exosome or siBTK@Exosome alone, demonstrating synergistic therapeutic role of ISOIM and si-BTK. Besides, ISOIM/siBTK@Exosome can accelerate T cells activation and prevent macrophage M2 polarization in vitro. Administration of ISOIM/siBTK@Exosome to tumor-bearing mice significantly inhibited tumor growth and prolonged survival. The ISOIM/siBTK@Exosome was biocompatible and biosafe in vivo without damage on the major organs in H&E staining. The prepared ISOIM/siBTK@Exosome may provide novel targeted therapeutic strategy to be applied in the clinical management of patients with DLBCL.
    Keywords:  B cell lymphoma; BTK; Drug delivery system; Exosome; Isoimperatorin; Non-hodgkin lymphoma
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102267
  28. World J Hepatol. 2026 Jan 27. 18(1): 114542
    Enhanced surgical tolerance of schistosomiasis-induced fibrotic liver following treatment with Ziziphus plant extract.
    Thamer H Alghamdi.
       BACKGROUND: Ziziphus spina-christi leaf extract (ZSCLE) can be used to treat hepatic schistosomiasis. However, its role as an anti-inflammatory and anti-proliferative agent remains unexplored.
    AIM: To assess the therapeutic potential of ZSCLEs in hamsters infected with Schisto som mansoni (S. mansoni) undergoing 50% liver resection (LR).
    METHODS: Fifty hamsters were divided into five groups (10 hamsters each), with group I serving as the control; group II received ZSCLE treatment only; group III was infected with S. mansoni but was untreated; group IV was infected with S. mansoni and received ZSCLE treatment; group V was infected with S. mansoni and underwent ZSCLE treatment and 50% LR. Each group was analyzed using DNA flow cytometry, and oxidative stress (nitric oxide levels), inflammatory markers (tumor necrosis factor-α and interferon-γ), and liver biomarkers were assessed. Histopathological examination was conducted for all groups.
    RESULTS: Compared with the infected untreated group, the ZSCLE-treated group showed a significant 70.2% reduction in hepatic tissue egg load (3459.5 ± 191.3 vs 1032 ± 25.1, P < 0.001), and the ZSCLE-treated group that underwent surgical resection showed a 71.8% decrease (2021.7 ± 190.2 vs 7193.3 ± 103.4, P < 0.001). Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin levels were higher in group III than in group I, group IV, and group V (P < 0.0001). The liver regeneration rate (%) was significantly higher in group IV and group V than in group III (median values: 45.18%, 47.93% vs 28.31%). Pathological examination revealed fewer granulomas in group V.
    CONCLUSION: ZSCLE-LR is a potent agent against schistosomiasis-induced hepatic damage, exhibiting a significant role in promoting hepatic regeneration. Further molecular-level studies are warranted to investigate the phytochemical properties of ZSCLE and its potential applications in managing schistosomiasis-induced hepatic fibrosis.
    Keywords:  Interferon-γ; Liver resection; Oxidative stress; Schistosomiasis; Tumor necrosis factor-α; Ziziphus spina-christi leaf extract
    DOI:  https://doi.org/10.4254/wjh.v18.i1.114542
  29. J Control Release. 2026 Jan 30. pii: S0168-3659(26)00077-5. [Epub ahead of print]392 114676
    An elastase-responsive "plug-and-play" quercetin-loaded engineered extracellular vesicle platform anchored with anti-PRDX1 antibody for severe acute pancreatitis therapy.
    Wenjie Xu, Qiong Liu, Junyong Wu, Beibei Cui, Yucheng Tang, Xinyan Hao, Ruyue Han, Hai Huang, Mengen Guo, Xuyang Hou, Jun He.
      Severe acute pancreatitis (SAP) is a lethal inflammatory disease driven by a severely disregulated redox state, in which Peroxiredoxin 1 (PRDX1) acts as a key but paradoxical regulator. PRDX1 is a protective intracellular antioxidant, however, it acts as a pro-inflammatory DAMP extracellularly. To address this, we developed a "plug-and-play" therapeutic platform. Considering the microenvironment in SAP, we first engineered HEK-293 T cells to overexpress a CD63-Z domain fusion protein, yielding extracellular vesicles (EVs) capable of high-affinity binding to the Fc region of various antibodies. We then armed these EVs with an anti-PRDX1 antibody via an elastase-responsive linker and co-loaded them with quercetin (Ab-Fc-EL-EV@Que). After active pancreatic targeting, locally concentrated elastase triggered antibody release from the Ab-Fc-EL-EV@Que. to neutralize extracellular PRDX1, which has been confirmed to activate the TLR/NF-κB pathway in macrophages, thereby suppressing the inflammatory cascade. Subsequently, the antibody-detached EVs were internalized by acinar cells, delivering Que. to promote intracellular PRDX1 acetylation, enhance antioxidant capacity, and ultimately protect acinar cells from ferroptosis and apoptosis. This work not only offers a potent, multi-mechanistic modality for SAP by resolving the PRDX1 paradox but also establishes a highly adaptable "plug-and-play" platform for tailored therapies against other complex diseases.
    Keywords:  Elastase-responsive; Engineered extracellular vesicle; Prdx1; Quercetin; Severe acute pancreatitis
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114676
  30. Front Microbiol. 2025 ;16 1696524
    Engineered probiotics for inflammatory bowel disease therapy: mechanisms, delivery strategies, and precision medicine.
    Xiaohua Wang, Yindi Cheng, Jiahui Huang, Feixuan Xu, Jian Jiang, Nonthaneth Nalinratana, Litong Jin, Ying Xue.
      Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is a prevalent chronic gastrointestinal disorder. Conventional therapies are often limited by adverse effects and suboptimal long-term efficacy. Probiotics have emerged as promising therapeutic alternatives for IBD because of their ability to modulate the gut microbiota, reinforce intestinal barrier integrity, and regulate immune responses. However, their clinical translation is hampered by challenges within the harsh gastrointestinal milieu, including low viability, poor colonization, and insufficient target specificity. This review focuses on the engineering of probiotics designed to overcome these limitations for IBD management. We outline the therapeutic potential and mechanisms of action of probiotics in IBD, with a critical emphasis on discrepancies between preclinical and clinical observations. We subsequently discuss the drawbacks of conventional probiotic therapies, highlighting gaps between in vitro efficacy and in vivo performance. We then highlight cutting-edge engineering strategies, encompassing advanced encapsulation techniques, genetic engineering approaches, novel delivery systems, and molecular-targeting modifications, with quantitative comparisons of their advantages, limitations, and translational potential. The application of these engineered probiotics specifically in UC and CD treatment is explored, with detailed analyses of preclinical models and clinical trials. We also address personalized interventions tailored to individual gut microbiome profiles. Despite significant promise, critical challenges remain, including long-term safety, stability, and accurate prediction of therapeutic responses for engineered probiotics in IBD. Nevertheless, with ongoing advancements in gene editing, synthetic biology, and microbial safety engineering, engineered probiotics represent a promising direction in IBD therapy that will enable more precise, effective, and personalized treatment modalities, provided that safety, reproducibility, and regulatory compliance are prioritized.
    Keywords:  Crohn’s disease; biosafety; engineered probiotics; genetic engineering; gut microbiome; inflammatory bowel disease; precision medicine; ulcerative colitis
    DOI:  https://doi.org/10.3389/fmicb.2025.1696524
  31. Adv Mater. 2026 Feb 01. e22010
    Polysaccharide Engineered Nanozymes Target Inflammation for Alleviating Colitis-Associated Mental Disorders via Microbiome-Gut-Brain Axis.
    Gen Wei, Hui Zhang, Shuang Zhao, Jian Jiang, Chen Liu, Peng Li, Yaya Ni, Hua Dai, Lei Fan, Hui Wei, Juqun Xi.
      Molecular therapies for colitis-associated mental disorders show limited efficacy because they usually focus on a single pathway and exhibit substantial off-target toxicity toward healthy tissues. To tackle this limitation, bioinformatic approaches are employed to predict that inflammation and metabolism may be potential targets for Fucoidan. Guided by this prediction, we develop oral polysaccharide engineered nanozymes, Fucoidan-cerium nanocomplexes (FucCeNCs), which are capable of targeting the inflamed colon through electrostatic interactions, exerting anti-inflammatory effects, and concurrently regulating gut microbiota-derived metabolism. In a murine model of ulcerative colitis-associated mental disorders, FucCeNCs show anti-inflammatory and gut barrier-protective effects, thereby suppressing microglial/astrocytic overactivation and preserving neuronal integrity through the transmission of anti-inflammatory cytokines via gut-brain axis. Importantly, FucCeNCs restore gut microbial homeostasis through increasing the relative abundance of probiotics and reducing proportions of pathogens. This shift results in a marked attenuation of abnormal amino acid biosynthesis and metabolism in fecal metabolites, which in turn leads to elevated levels of bioactive metabolites such as homovanillic acid and γ-aminobutyric acid. These metabolites ultimately attenuate neuroinflammation via the microbiome-gut-brain axis, ameliorating depression- and anxiety-like behaviors. These results identify microbiome-gut-brain axis as pivotal therapeutic target for colitis-associated mental disorders therapy, which can be addressed by polysaccharide engineered nanozymes.
    Keywords:  colitis‐associated mental disorders; gut inflammation; gut microbiota‐derived metabolism; microbiome‐gut–brain axis; polysaccharide engineered nanozymes
    DOI:  https://doi.org/10.1002/adma.202522010
  32. J Biosci. 2026 ;pii: 3. [Epub ahead of print]51
    Preconditioned umbilical-cord mesenchymal stem-cell exosomes preserve functional hepatocytes in bile duct-ligated rats through alternate miRNA signaling rather than HGF signaling.
    Ratna Puspita, Ahmad Aulia Jusuf, Radiana Dhewayani Antarianto, Andri Pramesyanti Pramono.
      Biliary atresia (BA) is a prominent cause of liver cirrhosis in pediatric patients with a high pediatric end-stage liver disease (PELD) score and a Laennec score of 4 at the Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia. Bile duct-ligated rat models have been used to mimic the clinical condition of BA partially. This study aims to evaluate the potential miRNAs of preconditioned umbilical-cord mesenchymal stem-cell exosomes (UC-MSC-exosomes) in comparison with the combined exosomes-HGF effect on liver histology, liver function, and hepatocyte-signaling in bile duct-ligated rats. Characterization of preconditioned UC-MSC-exosomes fulfilled the ISEV 2018 criteria. Liver histology showed trends of hepatocytes, inflammatory cells, and oval cell numbers returning to slightly below normal levels post-preconditioned UC-MSC-exosomes or the exosomes-HGF combination, with no statistically significant difference. A significant difference in bile duct proliferation post-preconditioned UC-MSC-exosomes or the exosomes-HGF combination was observed when compared with the control. Trends towards lower deposition of collagen around the porta area and total area fractions post-preconditioned UC-MSC-exosomes or the exosomes-HGF combination showed no statistically significant difference; however, there was a slightly lower total collagen area fraction in the exosomes-HGF combination group. Functional hepatocyte preservation was indicated by increased albumin expression and partially improved CYP3A4 levels post-preconditioned UC-MSC-exosomes or the exosomes-HGF combination. There was also a different trend in functional hepatocyte biochemical markers, SGOT (AST) and SGPT (ALT), between preconditioned UC-MSC-exosomes and the exosomes-HGF combination. NanoString microarray analysis of liver tissue and bioinformatics analysis were done to investigate in-depth hepatocyte signaling. miRNA profiling of the liver from preconditioned UC-MSC-exosomes identified the upregulation of hsa-miR-1-3p and hsa-miR-372-3p, which inhibit key signaling pathways, e.g., MAPK, PI3K-AKT, and NF-κB, and the downregulation of hsa-miR-520a-3p, which promotes hepatocyte proliferation and survival. miRNA profiles of the liver from the exosomes-HGF combination identified five different miRNA expressions (upregulated hsa-miR-144-3p, hsa-let7-5p, hsa-let7a-5p, hsa-let7e-5p, and hsa-miR-32-5p) and shared only one similar miR with the exosomes-treated liver (downregulated hsa-520a-3p). These miR differences contribute to the hepatocyte signaling in the exosomes-HGF combination group. Preconditioned UC-MSC-exosomes preserve functional hepatocytes in bile duct-ligated rats through alternate miR-mediated signaling rather than HGF signaling.
  33. Mater Today Bio. 2026 Apr;37 102789
    Alendronic acid modified PLGA drug delivery system loaded with 17β-Estradiol and vitamin D3 has anti-osteoporotic effect.
    Yonghui Wang, Sidi Zhang, Xinrun Ma, Donghao Hu, Junran Liu, Lu Wei, Xue Lei, Yan Hu, Fuyou Li, Yanhong Gao.
      Postmenopausal osteoporosis caused by estrogen deficiency often requires hormone replacement therapy (HRT), but its systemic side effects limit clinical application. Here, we developed a bone-targeted Poly (lactic-co-glycolic acid) (PLGA) nanocarrier modified with Alendronic acid (ADA) to co-deliver 17β-Estradiol (E2) and Vitamin D3 (VitD3), aiming to enhance efficacy and safety. The ADA-functionalized nanoparticles (E2+VD@PLGAIR780ADA) showed high drug loading (7.2 wt% for E2 and 2.3 wt% for VitD3), sustained release (>90 % over 48 h). In ovariectomized (OVX) mice, targeted delivery significantly improved bone mineral density, restored trabecular structure, and reduced serum bone resorption markers, while markedly alleviating E2-induced endometrial thickening. In vivo imaging confirmed selective bone accumulation. Mechanistically, co-administration of VitD3 and E2 elicits enhanced pro-osteogenic effects by virtue of VitD3-mediated Vitamin D Receptor (VDR) upregulation and amplified E2-induced estrogen receptor (ER) expression, which collectively drive robust activation of the PI3K/AKT/mTOR signaling cascade.This bone-specific nanoplatform offers a promising and safer strategy for osteoporosis therapy beyond conventional HRT.
    Keywords:  17β-Estradiol; Alendronic acid; Osteoporosis; Vitamin D3
    DOI:  https://doi.org/10.1016/j.mtbio.2026.102789
  34. Adv Healthc Mater. 2026 Feb 06. e05156
    Spatiotemporal Synergistic Effects of Injectable Biomaterials With Two Typical 3D Geometries on Macrophage Modulation for Enhanced Tissue Regeneration.
    Liangwei Si, Sijia Liu, Chen Gao, Zixuan Wang, Fei Xiong.
      Injectable biomaterials with immunomodulatory functions have become a promising strategy to facilitate tissue regeneration. Material geometry is known to influence macrophage attachment and phenotype, providing opportunities for the rational design of "immune-instructive" topographies to modulate macrophage function. Here, we developed a biomaterial systems consisting of two different "immune-instructives" 3D geometries: sphere-shaped microspheres (MSs) and rod-shaped short microfibers (MFs) to modulate macrophage function for tissue regeneration. In the injectable biomaterials, we found that varying ratios of MSs to MFs in the composites significantly influence macrophage recruitment and M2 polarization, with high ratios of MFs potentially inducing scar formation. Through a systematic comparison of the promotive effects on tissue regeneration between MSs and MFs, we discovered that MSs and MFs exhibited a spatiotemporal synergistic effect on immunomodulation for tissue regeneration. Specially, MS rapidly triggered the foreign body reaction after implantation and enhance macrophage infiltration. Subsequently, the recruited macrophages underwent morphological changes upon contact with MFs, activating autophagy and polarizing toward the M2 phenotype, thereby accelerating collagen deposition. The developed immunomodulatory composites provide a promising strategy for engineering injectable biomaterials with immunomodulatory function that demonstrates desirable stimulation for tissue regeneration.
    Keywords:  immunomodulatory; injectable biomaterials; macrophage polarization; microsphere; short microfibers; tissue regeneration
    DOI:  https://doi.org/10.1002/adhm.202505156
  35. bioRxiv. 2026 Jan 24. pii: 2026.01.24.701482. [Epub ahead of print]
    Mismatch type impacts interference and priming activities in the type I-E CRISPR-Cas system.
    Phong T Phan, Meric Ozturk, Elizabeth M Dougherty, Jerusha Ravishankar, Chaoyou Xue, Dipali G Sashital.
      Type I-E CRISPR-Cas systems direct RNA-guided interference against foreign nucleic acids using the CRISPR RNA (crRNA)-guided Cascade complex and Cas3 helicase-nuclease. DNA targeting by Cascade-Cas3 promotes priming, a mechanism that allows for rapid acquisition of new spacers within the CRISPR array. Target mutations in the PAM and PAM-proximal seed region can block interference but may still allow priming. Previous studies have suggested that target mutations to T and A are tolerated, but that C and G substitutions are deleterious to interference and priming, respectively. However, the contributions of the crRNA spacer sequence to mutational tolerance remain unclear. Here, we systematically tested the effects of crRNA seed sequences on mutational tolerance. We engineered four E. coli strains with variable spacer sequences and tested CRISPR interference and priming against a plasmid library for each strain. Consistent with prior studies, we observe that mutations to C or G in the seed can be highly deleterious, especially at positions 1, 2 and 4. However, the corresponding crRNA sequence also strongly impacts the level of defect, with rC-dC and rA/G-dG causing the largest defects in our plasmid library experiments. Using in vitro biochemistry, we observe that mismatch type at the first position of the seed affects Cas8 conformation, and results in reduction in the rates of both Cascade-target binding and Cas3 recruitment. Overall, our results reveal that although nucleotide identity of target mutations is an important determinant of type I-E CRISPR immunity, the crRNA sequence also strongly impacts immune outcomes upon target mutation.
    DOI:  https://doi.org/10.64898/2026.01.24.701482
  36. Beijing Da Xue Xue Bao Yi Xue Ban. 2026 Feb 18. 58(1): 10-21
    [miR-488-5p promotes osteogenic and neurogenic differentiation of rat bone marrow mesenchymal stem cells and enhances neuralized bone regeneration].
    L Zeng, K Cheng, Z Liu, J Li, J Yang, T Jiang.
       OBJECTIVE: To investigate the role of microRNA miR-488-5p, which showed increased expression after the disconnection of the inferior alveolar nerve, in promoting the osteogenic and neurogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs), as well as its effect on promoting the neuralized tissue engineered bone regeneration.
    METHODS: rBMSCs were subjected to in vitro neural or osteogenic differentiation induction cultures. The expression levels of miR-488-5p at different time points (days 0, 2, 4, and 7) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). miR-488-5p overexpression or low expression in rBMSCs was achieved by transfection with miR-488-5p mimics or inhibitors. Four groups, the miR-488-5p mimics, the miR-488-5p inhibitor, and their respective negative controls (NC), were established to investigate the effects of miR-488-5p on the neural differentiation and osteogenic differentiation of rBMSCs.A 5 mm diameter, full-thickness circular critical bone defect was created in the rat calvaria. The rats were treated with light-cured gelatin methacryloyl (GelMA) seeded with rBMSCs. The rats were divided into four groups: ①BLANK group: GelMA; ②BMSCs group: GelMA + rBMSCs; ③NC-BMSCs group: GelMA + rBMSCs transfected with miR-488-5p mimics NC; and ④miR-488-5p-BMSCs group: GelMA + rBMSCs transfected with miR-488-5p mimics. Specimens were obtained 4 and 8 weeks after surgery, and micro-CT was performed to measure and analyze bone mineral density (BMD), bone volume/total volume (BV/TV), bone surface area/total volume (BS/TV) and trabecular number (Tb.N). The effects of neuralized tissue engineering bone formation in the defect area were assessed using Hematoxylin-Eosin (HE) staining, Masson staining, and tissue immunofluorescence staining of the nerve-specific protein soluble protein-100 (S100).
    RESULTS: As rBMSCs progressed toward neural or osteogenic differentiation, miR-488-5p expression increased significantly from day 0 to day 7. Regarding neural differentiation, the mimics group showed increased expression of neural-related genes and proteins compared with the mimics NC group, while the opposite result was observed in the inhibitor group. As for osteogenic differentiation, the mimics group showed increased expression of osteogenic genes and proteins, more intense alkaline phosphatase (ALP) and alizarin red staining (ARS) staining, and enhanced ALP activity compared with the mimics NC group, while the opposite result was observed in the inhibitor group. 4 and 8 weeks after critical calvarial defect construction in rats, the BLANK group had the least amount of new bone formation, while the BMSCs group and the NC-BMSCs group had similar and intermediate amounts of new bone formation. The miR-488-5p-BMSCs group had the most new bone formation. At 4 weeks, the BMD [(0.63±0.05) g/cm3 vs. (0.51±0.03) g/cm3], BV/TV (33.17%±6.43% vs. 18.11%±1.52%), BS/TV [(3.43±0.69) /mm vs. (2.46±0.20) /mm], and Tb.N [(0.92±0.21) /mm vs.(0.59±0.07) /mm] in the miR-488-5p-BMSCs group were significantly higher than those in the NC-BMSCs group. At 8 weeks, the BMD [(0.80±0.04) g/cm3 vs. (0.68±0.04) g/cm3], BV/TV (56.69%±6.22% vs. 42.36%±3.86%), and the number of S100-labeled nerve cells around the new bone (46.33±4.04 vs. 26.00±3.61) in the miR-488-5p-BMSCs group was also significantly higher than that in the NC-BMSCs group.
    CONCLUSION: miR-488-5p promoted the osteogenic and neurogenic differentiation of rBMSCs and promoted the formation of neuralized tissue-engineered bone in rat calvarial defects.
    Keywords:  Bone marrow mesenchymal stem cells; Neuro-bone tissue engineering; Neurogenic differentiation; Osteogenic differentiation; miR-488-5p
  37. ACS Sens. 2026 Feb 05. XXX
    DISCERN: Dual-Aptamer-Initiated Sensing Circuit via Engineered Nanozyme for Leukemia Stem Cells Phenotyping.
    Hai Shi, Lu Liu, Ying Shen, Yunlong Xiao, Renwu Mu, Suzhen Zhai, Bin Zhang, Xiaoyan Yang, Chunlin Zhang.
      Leukemia stem cell (LSC) phenotyping offers significant potential to enhance minimal residual disease (MRD) monitoring in acute myeloid leukemia (AML), improving therapeutic evaluation and relapse prediction. However, current approaches lack the sufficient sensitivity and specificity to reliably detect rare chemotherapy-resistant LSCs (crLSCs) or identify stem-like phenotypic states, limiting clinical translation. Here, we develop DISCERN (Dual-Aptamer-Initiated Sensing Circuit via Engineered Nanozyme), a colorimetric platform for ultrasensitive LSC phenotyping. DISCERN employs a dual-aptamer system targeting colocalized surface markers (CD33 and CD123) for high-specificity recognition. Its exceptional sensitivity (limit of detection <10 cells/mL) is achieved by a localized catalytic cascade: target-binding initiates on-site rolling circle amplification (RCA), which in turn templates the assembly of PCN-222(Fe) nanozymes that generate amplified colorimetric signals. We demonstrate that DISCERN can track phenotypic plasticity in leukemia cells and identify stem-like subsets in leukemia xenograft models. This cost-effective and robust platform provides a promising tool for AML risk stratification, relapse prediction, and precision therapy.
    Keywords:  engineered nanozyme; leukemia stem cells; minimal residual disease; phenotyping; sensing circuit
    DOI:  https://doi.org/10.1021/acssensors.5c03906
  38. Acta Biomater. 2026 Jan 28. pii: S1742-7061(26)00067-X. [Epub ahead of print]
    Engineered Acid-Regulating Liposomal Nanovesicles for Synergistic Photodynamic Pyroptosis and Immunotherapy.
    Xiangmei Chen, Mengjie Ye, Yujie Wen, Lingling Li, Xiaoxiao Shi, Zhigang Xu.
      Gasdermin-mediated pyroptosis has emerged as a promising mechanism in cancer immunotherapy, however, its efficacy is often limited by inefficient activation within the immunosuppressive tumor environment. Herein, we generated an acid-regulating biomimetic liposomal nanovesicle (L-P-Cn-U) for the co-delivery of a photosensitizer prodrug (P-Cn) and a carbonic anhydrase IX (CAIX) inhibitor (U-104). By conducting efficacy screening of various P-Cn prodrugs within the L-P-Cn-U system, we identified L-P-C16-U with identical lipid tail structures, as the optimal candidate due to its superior colloidal stability and ROS generation efficiency. Our cellular and murine model studies demonstrated that L-P-Cn-U-mediated pyroptosis and immunogenic cell death could convert immunologically cold tumors into hot tumors, thereby enhancing antitumor immunity and concurrently inhibiting tumor cell migration. Mechanistic investigation revealed that the acid-triggered U-104 release from L-P-Cn-U augmented intracellular acidity through CAIX inhibition, which subsequently attenuated PI3K-Akt/mTOR signaling. This result enhances O2-dependent ROS production and establishes a negative feedback loop for CAIX expression. Collectively, our findings provide a combinatorial strategy that integrates pyroptosis-focused therapy with metabolic regulation, offering a broadly applicable conception to augment cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Herein, we report the rational design and synthesis of a novel class of biomimetic liposomes by integrating chemically engineered pH-responsive lipids (L-pH) with lipid-like photosensitizer prodrugs (P-Cn). Characterization studies demonstrated an optimal construct (L-P-C16) with identical lipid tails, showing superior stability and reactive oxygen species production. This optimized nanovesicle was subsequently co-loaded with the carbonic anhydrase inhibitor U-104. The resulting L-P-C16-U system was adequately investigated and shown to effectively synergize photodynamic therapy and immunotherapy. Our work provides new insights into liposome engineering strategies for combination tumor therapy.
    Keywords:  liposomes; pH-responsive; photodynamic therapy; pyroptosis; tumor immunity
    DOI:  https://doi.org/10.1016/j.actbio.2026.01.052
  39. Neurosurg Focus. 2026 Feb 01. 60(2): E5
    Engineered neuroglial organoids as living neural interfaces for restorative neurosurgery.
    Vikas N Vattipally, Patrick Kramer, Katholiki Troumouchi, Shuhei Shiino, Nada Abouelseoud, Kaustubh Joshi, Risheng Xu, Nicholas Theodore, Henry Brem, Chetan Bettegowda, Lauren L Jantzie, Shenandoah Robinson, Tej D Azad, Annie Kathuria.
      Acute and chronic CNS pathologies that result in tissue loss remain among the most intractable problems in neurosurgery, with current treatments focused on stabilization and neuroprotection rather than structural repair. Neural interfaces such as recording, stimulating, or replacing neural activity have demonstrated value in restoring function via prostheses and brain-computer interfaces, yet these approaches are constrained by electrode design, bandwidth, and limited biological integration. Engineered neuroglial organoids offer a complementary, biologically based interface strategy. Derived from pluripotent stem cells, neuroglial organoids arrive as 3D constructs containing neurons and glia in intrinsic architecture, capable of vascularization, synaptic connectivity, and integration with host tissue. Building on dissociated stem cell suspensions, organoids act not only as reservoirs of cells but also as living neural interfaces, receiving inputs from host circuits and generating functional outputs. Preclinical studies have demonstrated that transplanted organoids can couple to host sensory pathways, respond to stimulation, and support recovery of motor and cognitive functions. Moreover, emerging work coupling organoid grafts to brain-computer interfaces highlights the potential for closed-loop biological electronic systems, in which engineered devices provide precise recording and stimulation while organoids contribute adaptive, active biological circuits. This combination allows real-time bidirectional communication, allowing the graft to be both monitored and adapted to structurally and functionally integrate into host tissue. In this review, the authors examine neuroglial organoid transplantation through the lens of neural interfacing. They outline lessons from non-CNS organoid transplantation, summarize neurotrauma studies where grafts engage host circuits, and highlight opportunities to integrate organoids with electrodes, stimulation paradigms, and computational models. They also discuss challenges, namely vascularization, immune tolerance, surgical delivery, and manufacturing standards, that parallel those in neural device translation. For neurosurgeons, the appeal of neuroglial organoids lies not only in tissue replacement but in establishing a new class of biological neural interfaces, extending the reach of restorative neurosurgery. By merging living constructs with engineered devices, organoid-based strategies may enable hybrid restorative systems that restore function after neurological injury and disease.
    Keywords:  Alzheimer’s disease; ischemic stroke; neuroglial organoids; restorative neurosurgery; stem cells; traumatic brain injury
    DOI:  https://doi.org/10.3171/2025.11.FOCUS25911
  40. Open Vet J. 2025 Nov;15(11): 5760-5771
    Liposomes from red betel (Piper crocatum) extract: A new approach in the delivery of anti-inflammatory drugs.
    Siti Imroatul Maslikah, Heri Prayitno, Muhaimin Rifa I, Warsito Warsito, Muhammad Sasmito Djati.
       Background: Piper crocatum extract contains bioactive compounds, such as flavonoids and phenolics, that exhibit anti-inflammatory activity by inhibiting cyclooxygenase-2, suppressing nuclear factor kappa B, and modulating pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6. Liposomal encapsulation enhances these compounds' stability, bioavailability, and targeted delivery, making it a promising strategy for anti-inflammatory drug development.
    Aim: This review evaluates the potential of P. crocatum liposomes as drug carriers for inflammatory disorders and identifies key research gaps.
    Methods: A systematic literature review was conducted using the Scopus database, following the PRISMA 2020 protocol and assisted by Parsif.ai for screening and data extraction.
    Results: Piper crocatum liposomes improved the physicochemical stability and therapeutic activity of encapsulated compounds, exhibiting enhanced antibacterial and anti-inflammatory effects. Their ability to modulate inflammation at the molecular level and deliver agents to specific sites demonstrates strong potential for therapeutic and preservative applications.
    Conclusion: Piper crocatum liposomal formulations offer a stable and effective delivery system for inflammation-related therapies, supporting further investigation into their clinical and pharmaceutical applications.
    Keywords:  Anti-inflammatory drug; Liposome; Red betel (Piper crocatum); Systematic literature review (SLR)
    DOI:  https://doi.org/10.5455/OVJ.2025.v15.i11.31
  41. J Cell Mol Med. 2026 Feb;30(3): e71050
    Exosomal HMGB1 Orchestrates NSCLC Progression and Immunosuppressive Macrophage Polarisation Through the TLR4/NF-κB/IL-6/STAT3 Signalling Cascade.
    Jia-Ru Huang, Wen-Chao Gu, Ya-Ping Yuan, Jun-Xia Yang, Yan Chen, Xiao-Xia Guo, Wei Ding.
      High mobility group box 1 (HMGB1), a prototypical alarmin and chromatin-binding protein, has emerged as a critical mediator of tumour-associated inflammation and immune regulation. Although its soluble form has been implicated in various malignancies, the functional contribution of HMGB1 encapsulated within exosomes remains incompletely understood, particularly in the context of non-small-cell lung cancer (NSCLC). We profiled exosomal HMGB1 levels in the peripheral blood of 80 clinically annotated NSCLC patients and correlated its abundance with metastatic burden and survival outcomes. Functional experiments using HMGB1-overexpressing NSCLC cell lines were conducted to assess proliferative, migratory and stemness-associated phenotypes in vitro, alongside tumorigenicity and drug responsiveness in vivo. Mechanistic interrogation of the TLR4/NF-κB/IL-6/STAT3 signalling axis was performed via western blotting, ELISA, immunofluorescence and targeted pharmacologic inhibition. The impact of exosomal HMGB1 on macrophage plasticity was evaluated using THP-1-derived macrophage models, and therapeutic relevance was validated in murine tumour models under immunotherapy and chemotherapy regimens. Circulating exosomal HMGB1 levels were significantly elevated in patients with metastatic NSCLC and strongly correlated with poor prognosis. Exosomal HMGB1 markedly enhanced tumour cell proliferation, motility and self-renewal capacity, while promoting chemoresistance and immune evasion. Mechanistically, HMGB1-enriched exosomes activated the TLR4/NF-κB axis, elevating IL-6 secretion and subsequent STAT3 phosphorylation. These effects were further linked to the polarisation of macrophages towards an immunosuppressive M2 phenotype. Therapeutically, cotargeting STAT3 signalling overcame exosomal HMGB1-mediated resistance to paclitaxel in vivo. Our findings delineate a previously unrecognised exosome-mediated mechanism by which HMGB1 drives NSCLC progression and modulates the tumour immune microenvironment. Exosomal HMGB1 not only serves as a potential prognostic biomarker but also represents a tractable target for enhancing the efficacy of immuno- and chemotherapeutic strategies in NSCLC.
    Keywords:  HMGB1; IL‐6; NSCLC; STAT3; TLR4/NF‐κB; macrophage
    DOI:  https://doi.org/10.1111/jcmm.71050
  42. Biotechnol J. 2026 Feb;21(2): e70187
    A Pull-Block Metabolic Engineering Strategy for High-Yield and High-Purity Hyoscyamine Production in Atropa belladonna.
    Lingjiang Zeng, Hongting Chen, Mengling Wen, Siyuan Liao, Chunxian Yang, Junlan Zeng, Min Chen, Zhihua Liao, Sheng Tong.
      Hyoscyamine, an active tropane alkaloid primarily extracted from the medicinal plant Atropa belladonna, exhibits analgesic and sedative effects and is widely used as a precursor in pharmaceutical formulations. However, the low yield of hyoscyamine and the complex composition of tropane alkaloids in wild-type A. belladonna plants pose significant challenges for industrial production, making it imperative to modify the metabolic pathway to enhance hyoscyamine yield and purity. In this study, a pull-block metabolic engineering strategy, which enhanced hyoscyamine biosynthesis by co-overexpressing AbPYKS, AbCYP82M3, AbUGT1, AbLS, and AbHDH genes and blocked the metabolic diversion of hyoscyamine by deleting the AbH6H gene, was employed. During this process, the glyphosate resistance gene G2-EPSPS was introduced into A. belladonna. Ultimately, the engineered plants with glyphosate resistance were obtained, which showed significantly enhanced hyoscyamine yield (6.511 vs. 0.989 mg/g DW in leaves) and purity (the absence of anisodamine and scopolamine) relative to the wild-type. These results not only enrich the germplasm resources of A. belladonna but also hold promise for advancing the production of the hyoscyamine-based pharmaceuticals. Next, we will evaluate these engineered plants under field conditions for both hyoscyamine production and growth/development.
    Keywords:  Atropa belladonna; glyphosate resistance; hyoscyamine; multigene co‐overexpression; pull‐block strategy
    DOI:  https://doi.org/10.1002/biot.70187
  43. J Nanobiotechnology. 2026 Feb 05. 24(1): 131
    Healthy young human plasma-derived exosomes enhance neural stem cell therapy by suppressing pyroptosis via TXNIP/NLRP3 after intracerebral hemorrhage.
    Jiao Chen, Ziqiang Chen, Fuan Zhang, Pangbo Wang, Qian Zhang, Haomiao Wang, Fengchun Zhao, Huanhuan Li, Ran Luo, Ning Ding, Shengtao Yao, Rong Hu.
       BACKGROUND: Neural stem cells (NSCs) transplantation holds promise for intracerebral hemorrhage (ICH) treatment, but its efficacy is limited by poor survival and aberrant differentiation of grafted cells. Here, we demonstrate that exosomes derived from healthy young donor plasma, a natural nanomaterial protect NSCs against pyroptosis, a gasdermin-dependent inflammatory cell death process triggered by ICH.
    METHODS: Plasma exosomes were extracted from young (Y-exo) and old (O-exo) healthy individuals and characterized. An in vitro model of ICH was established by hemin treatment. For the in vivo study, the mouse ICH model was induced by autologous blood, a combined transplantation of Y-exo and NSCs was then performed as the therapeutic intervention. The protective effects of exosomes on NSCs were assessed via western blotting, immunofluorescence, ELISA, qPCR, and Calcein/PI detection. The therapeutic effects of combined transplantation of Y-exo and NSCs on ICH mice were evaluated through in vivo imaging systems and a series of behavioral tests.
    RESULTS: Exosomes derived from young plasma exert protective effects by supporting NSC survival, boosting their proliferative and differentiation capacity in vitro, and ameliorating the peri-hematoma microenvironment in vivo. Strikingly, the efficacy of Y-exo is superior to that of O-exo. Subsequent studies will use Y-exo, in vitro, the Y-exo exerted their protective effects by inhibiting the NLRP3/Caspase-1/GSDMD-mediated pyroptotic pathway and reducing the release of inflammatory cytokines. In vivo, co-transplantation of NSCs and Y-exo enhanced NSCs survival, proliferation, and beneficial differentiation toward neuronal and oliodendroglial lineage while attenuating pyroptosis of NSCs and peri-hematoma tissue. Behavioral tests indicated that mice in the co-transplantation group exhibited superior functional recovery. MiRNA sequencing identified miR-16-5p as a key mediator enriched in Y-exo, which targeted TXNIP to disrupt NLRP3 inflammasome activation. Genetic and pharmacological interventions confirmed that miR-16-5p/TXNIP/NLRP3 signaling pathway is essential for Y-exo's anti-pyroptotic effects.
    CONCLUSIONS: Our study elucidates a previously unidentified mechanism whereby Y-exo improve neurological outcomes by alleviating the peri-hematoma inflammatory microenvironment, suppressing pyroptosis in transplanted stem cells, and altering their differentiation fate. This study highlights the potential of synergistic strategy to optimize NSCs-based therapy for stroke by combining youth-derived factors, offering new insights into regenerative therapeutics for neurological disorders.
    Keywords:  Exosome; Intracerebral hemorrhage; Natural nanomaterial; Neural stem cells; Pyroptosis
    DOI:  https://doi.org/10.1186/s12951-026-04099-6
  44. Scand J Immunol. 2026 Feb;103(2): e70095
    Immunotherapy for Type 2 Diabetes: Mechanisms and Therapeutic Advances.
    Ravichandran Sanjai, Kunka Mohanram Ramkumar.
      Diabetes mellitus (DM) is a chronic metabolic disorder characterised by persistent hyperglycemia, systemic metabolic dysfunction and insulin resistance (IR). Recent progress in the interplay between the immune system and metabolism highlights the critical role of immune dysregulation in the pathogenesis of IR and type 2 diabetes mellitus (T2DM). This review explores the immunopathogenic mechanisms underlying IR and the potential immunotherapies to modulate these pathways, with a focus on immune cells, inflammatory mediators and immune checkpoint regulation. Recent advances in immunotherapy have opened new avenues for restoring metabolic homeostasis and improving insulin sensitivity. Targeted approaches, including monoclonal antibodies against TNF-α, IL-1β and IL-6, have been reported to have antifibrotic and anti-inflammatory effects, reducing inflammation-driven insulin resistance. Additionally, inhibitors of NF-κB, JAK/STAT and JNK signalling pathways have been reported to enhance insulin sensitivity. Immunoregulatory therapeutics using MSC (mesenchymal stem cell) and Treg (regulatory T cell) therapy and cytokine vaccine-based vaccines are emerging as innovative therapeutic options for T2DM. Despite these advances, problems such as immune-related toxic reactions, patient and individual-specific variability, and the requirement for precision medicine approaches persist as obstacles to translational application from the clinics to industry levels. In this review, an overview of preclinical and clinical evidence for immunotherapeutic approaches to IR is described, and recommendations for future developments in integrating these therapies into personalised diabetes management are provided. Targeting immune-mediated inflammation with immunotherapies can lead to a new era in T2DM therapy, which will provide new approaches to enhance insulin sensitivity and glycemic control.
    Keywords:  immune cells; immunotherapy; inflammation; insulin resistance
    DOI:  https://doi.org/10.1111/sji.70095
  45. Mol Ther Nucleic Acids. 2026 Mar 12. 37(1): 102837
    Liver-specific delivery of MDM2 antisense oligonucleotides counteracts diet-induced metabolic-dysfunction-associated steatotic liver diseases.
    Md Moinul Hoque, Mengjie Kong, Xinyi Yuan, Xiangyu Zhou, Steve Ting-Yuan Yeh, Kekao Long, Huige Lin, Kenneth King Yip Cheng.
      Metabolic-dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of pathogenic conditions ranging from steatosis, inflammation, and fibrosis with limited treatment options. We previously demonstrated an upregulation of hepatic murine double minute 2 (MDM2) in human subjects with MASLD. Genetic deletion of hepatic MDM2 and pharmacological inhibition of systemic MDM2 improves steatosis and fibrosis in MASLD mouse models. In this study, we further developed and investigated the therapeutic potential of a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide targeting MDM2 (GalNAc-Mdm2ASO) in two distinct dietary-induced mouse models of MASLD: a high-fat-high-cholesterol (HFHC) diet and a choline-deficient, L-amino-acid-defined, high-fat diet (CDAHFD). In the HFHC-induced MASLD model, GalNAc-Mdm2ASO not only alleviated liver injury, steatosis, and fibrosis but also improved obesity-related insulin resistance and hyperlipidemia. The hepatoprotective effects of GalNAc-Mdm2ASO treatment were associated with a reduced accumulation of hepatic cholesterol, diacylglycerol, and ceramide, which are known to trigger MASLD. In CDAHFD-induced MASLD mouse model, GalNAc-Mdm2ASO significantly mitigated hepatic inflammation, cholesterol accumulation, and fibrosis but not triglyceride accumulation. Overall, we prove hepatic inhibition of MDM2 using GalNAc-Mdm2ASO as a promising therapeutic agent for MASLD in two rodent models with distinct pathogenesis.
    Keywords:  ASOs; MASLD; MDM2; MT: Oligonucleotides: Therapies and Applications; RNA therapeutic; antisense oligonucleotides; liver-targeted therapy
    DOI:  https://doi.org/10.1016/j.omtn.2026.102837
  46. Cell Rep Med. 2026 Feb 05. pii: S2666-3791(25)00618-4. [Epub ahead of print] 102545
    Programmable iPSC-derived CAR-NK vesicles remodel the immune microenvironment and eradicate tumors.
    Hao Zhang, Shenglong Li, Chongzhong Liu, Xiangdong Gongye, Han Li, Yiyi Ji, Cheng-Wei Ju, Wenzhen Jia, Xing Niu, Yujing Guan, Xiangyu Zhai, Bin Jin, Peng Xia.
      Chimeric antigen receptor (CAR) cell therapy transforms hematologic cancer treatment but remains limited in solid tumors due to stromal barriers and an immunosuppressive tumor microenvironment that restricts immune cell infiltration. To address these barriers, we develop a cell-free therapeutic platform based on CAR-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) extracellular vesicles (CAR-iNEVs), which retain tumor-targeting capability without reliance on live-cell delivery. CAR-iNEV demonstrates potent antitumor activity and excellent tolerability across multiple xenograft and patient-derived models. Mechanistically, CAR-iNEV directly eliminates tumor cells and remodels the tumor microenvironment by promoting pro-inflammatory macrophage polarization, thereby enhancing host innate antitumor immunity. CAR-iNEV also functions cooperatively with immune checkpoint blockade, and combined treatment with CAR-iNEV and CD47 inhibition increases tumor clearance and induces long-term immunological memory in surviving mice. These findings support the therapeutic potential of CAR-iNEV for solid tumors through coordinated tumor targeting and immune microenvironment modulation.
    Keywords:  cell-free cancer immunotherapy; engineered extracellular vesicles; iPSC-derived CAR-NK extracellular vesicles; solid tumor immunotherapy; tumor microenvironment remodeling
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102545
  47. Iran J Basic Med Sci. 2026 ;29(1): 90-100
    Parthenolide attenuated the endometriosis-like lesions by activating autophagy and suppressing NLRP3 inflammasome activity.
    Luhongyuan Jin, Tingting Fu, Chi Chi, Jiayi Zhou, Jun Lin, Wenjie Hou.
       Objectives: Parthenolide (PTL) has significant anti-inflammatory and immunomodulatory effects, but its regulatory mechanisms in endometriosis (EMs) remain unclear. This study aimed to systematically evaluate the effects of PTL on cellular models and a murine EMs model, with a focus on its regulatory roles in autophagy and the NLRP3 inflammasome pathway.
    Materials and Methods: Human monocytic leukemia THP-1 cells, murine immortalized bone marrow-derived macrophages, and 30 female C57BL/6 mice were used. Autophagy-related proteins (Beclin1, LC3, p62) and inflammasome components (NLRP3, ASC, caspase-1) were detected by Western blotting, and the activation of the AMPK/ULK1 signaling pathway was assessed after treating with PTL at a concentration of 10 mg/ml for 1 hr. A murine EMs model was established by peritoneal implantation, followed by intraperitoneal injections of PTL (10 mg/ml). Immunohistochemical staining was performed to detect the expression of NLRP3, caspase-1, IL-1β, and GSDMD in ectopic lesions.
    Results: In vitro, PTL (10 mg/ml) significantly inhibited the activation of NLRP3, caspase-1-p20, IL-1β, and GSDMD, while increasing the phosphorylation levels of Beclin1 and AMPK/ULK1, and decreasing the expression of p62 and LC3, indicating enhanced autophagic flux. In vivo, PTL treatment markedly reduced the number, surface area, and weight of ectopic lesions in mice, and significantly suppressed the expression of inflammatory proteins in the lesions.
    Conclusion: PTL exerts its therapeutic effect on EMs by simultaneously activating autophagy through the AMPK/ULK1 signaling pathway and inhibiting the NLRP3 inflammasome and its downstream effectors.
    Keywords:  Autophagic; Endometriosis; Inflammasomes; Inflammatory response; NLRP3 protein; Parthenolide
    DOI:  https://doi.org/10.22038/ijbms.2025.90575.19521
  48. Transplantation. 2026 Feb 04.
    The First Pig-to-human Liver Xenotransplantation From Genetically Engineered Pig: A Game Changer in Bridging Therapy.
    Kasra Shirini, Mohamed B Ezzelarab, Alexandre Loupy, Raphael P H Meier, Burcin Ekser.
      
    DOI:  https://doi.org/10.1097/TP.0000000000005648
  49. Aging Dis. 2026 Jan 20.
    Osteoarthritic knee: Advances in Epidemiology, Emerging Etiopathologies and Adipose-Derived Stem Cells-based Therapies.
    Chian-Her Lee, Hsien-Tsung Lu, Ko-Ta Chen, Shen-Han Wu, Ying-Fong Su, Hui-Hsuan Ting, Ai-Chen Lee, Tin-Hsien Ko, Navneet Kumar Dubey.
      Knee osteoarthritis (KOA) is a degenerative disorder that affects the joint in a non-uniform and focal manner. It is characterized by the loss of hyaline articular cartilage, along with bony remodeling, capsular stretching, and weakness of periarticular muscles. It could be ascribed to etiological factors that are modifiable (obesity, joint injury, occupational hazards, physical inactivity), non-modifiable (age, female gender, and genetic predisposition, racial/ethnic differences), or emerging, such as high blood pressure, vitamin D deficiency, and metabolic syndrome, which might contribute to KOA pathophysiology. KOA treatment is multimodal, and recent years have witnessed a shift from primarily pharmacologic, surgical to regenerative therapies ones, due to limited advantages of the former and evidence that advanced approaches are more likely to suppress pathological symptoms in the long term and to delay or prevent functional decline. Minimally invasive stem cell-based alternatives such as adipose-derived stem cells (ADSCs) are being explored owing to their differentiation potential towards chondro-, osteo-, and adipogenic lineages for osteochondral reparative regeneration. ADSC-derived extracellular vesicles, particularly exosomes (ADSC-exo), are gaining prominence in the treatment of KOA due to their unique regenerative and anti-inflammatory properties. These exosomes offer several advantages compared to cellular interventions, being a cell-free therapeutic strategy, low immunogenicity, and potential to deliver bioactive molecules, promote anti-inflammatory effects, and cartilage repair and regeneration. ADSC-exo expresses miRNA and improved safety by regulating various pathways such as PI3K/AKT/mTOR signaling or Wnt/β-catenin signalling. Combinatorial approaches have also been applied with ADSCs, such as platelet-rich plasma, shockwave therapy, xanthan gum, hyperbaric oxygenation, and nanoparticles, which have shown significant improvements in alleviating KOA. Based on the above evidence, we have reviewed the advances in epidemiology, emerging etiopathologies, and ADSCs-based revitalization strategies for the osteoarthritic knee joint.
    DOI:  https://doi.org/10.14336/AD.2025.1401
  50. Front Immunol. 2025 ;16 1715593
    Telitacicept versus belimumab in proliferative lupus nephritis.
    Chang Wang, Man-Zhu Zhang, Xiao-Ying Yun, Ling-Xu Li, Jia-Wei Shan, Biao Liu, Bing Li.
       Background and objectives: Proliferative lupus nephritis (LN) is a severe pathological type of systemic lupus erythematosus with a high risk of progression to chronic kidney disease and end-stage renal disease. The prognosis of patients with proliferative LN has improved with advancements in treatment regimens. However, more effective molecular targeted therapies are still needed. This study aimed to evaluate the efficacy and safety of two novel biologics, telitacicept and belimumab, in the treatment of proliferative LN.
    Methods: Twenty-eight individuals diagnosed with proliferative LN (class III/IV ± V) were retrospectively enrolled at the Second Affiliated Hospital of Hainan Medical University between January 2021 and May 2025 and received either telitacicept (n=18) or belimumab (n=10) in conjunction with standard therapy for more than 24 weeks. The renal response rates were the evaluated outcome.
    Results: A total of 28 patients were enrolled, with 18 receiving telitacicept and 10 receiving belimumab. At 8 weeks, the telitacicept group presented a greater renal remission rate, with 8 patients (44.4%) achieving a complete renal response (CRR), 7 patients (38.9%) achieved partial renal response (PRR), and 3 patients (16.7%) showed no renal response (NRR). In contrast, only 6 patients (60%) achieved PRR in the Belimumab group. The renal remission rate at 8 weeks was significantly higher in the Telitacicept group compared to the Belimumab group (p=0.04). The telitacicept group also demonstrated greater improvements in the SLEDAI-2K score and complement C3 level. At 24 weeks, 72.2% of the telitacicept group achieved a CRR, whereas 60% of the belimumab group achieved a CRR, with no significant difference in renal response rates. Glucocorticoid and immunosuppressant use was successfully reduced in both groups. Additionally, both groups showed improvements in clinical parameters, but no significant difference was noted at 24 weeks.
    Conclusions: In this preliminary study, telitacicept appears to induce earlier renal and immunologic remission than belimumab, along with a potential reduction in the need for glucocorticoids and immunosuppressants. Further validation in larger studies is needed.
    Keywords:  BAFF; belimumab; lupus nephritis; renal remission rate; telitacicept
    DOI:  https://doi.org/10.3389/fimmu.2025.1715593
  51. Int J Biol Macromol. 2026 Jan 29. pii: S0141-8130(26)00537-4. [Epub ahead of print]345 150611
    The natural biological macromolecule sporopollenin capsules in biomedical applications: A systematic review (2015-2025).
    Muhammed Emin Bedir, Ali Bilgic, Ziya Aydin, Ahmed Nuri Kursunlu.
      Pharmaceutical materials science is shifting from synthetic nanotechnology toward naturally occurring micro-architectures. Sporopollenin Exine Capsules (SECs), derived from plant pollen, have emerged as promising candidates due to their evolutionary resilience and chemical stability. To evaluate their potential, a systematic review following PRISMA 2020 guidelines was conducted across Web of Science, Scopus, and PubMed (January 2015-July 2025). The screening process excluded agricultural and industrial applications to focus strictly on biomedical innovation, with risk of bias assessed using a modified Klimisch score for in vitro and preclinical studies. Of 2621 records, 51 original research articles met the inclusion criteria. Bibliometric analysis identified a research inflection point in 2014, marking a transition to applied materials science. Bio-sources have diversified beyond Lycopodium clavatum, with successful applications in oral drug delivery (n = 21), advanced biomedical targeting (n = 16), and material characterization (n = 14). Quantitative findings demonstrate loading efficiencies ranging from 3% to 79%, carrier sizes typically 10-75 μm, and tunable release kinetics engineered for targeted delivery. Overall, SECs demonstrate high biocompatibility, diverse loading capabilities, and functional advantages such as mucoadhesion. However, a "translational gap" remains between material characterization and clinical implementation. Future research must focus on standardized extraction protocols, comprehensive safety profiles, and clarification of regulatory pathways to enable clinical translation.
    Keywords:  Pollen exine capsules; Sporopollenin; Systematic review
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150611
  52. ACS Synth Biol. 2026 Feb 02.
    Engineering Mixotrophy in the Chemolithoautotrophic Cupriavidus necator through Hydrogenase Induction.
    Xin Pu, Caihong Weng, Yong Li, Biao Geng, Haiqian Yang, Xiaowei Peng, Yejun Han.
      Mixotrophy offers a promising strategy for biosynthesis by simultaneously utilizing organic carbon and CO2; however, mixotrophic microorganisms are rarely isolated outside of photoautotrophic microalgae. In this study, the chemoautotroph Cupriavidus necator H16 was found to preferentially consume fructose when coexisting with CO2 and H2, switching to utilization of only CO2 and H2 after fructose depletion. Transcriptomic analysis revealed significant differences in genes involved in energy metabolism, electron generation, and the respiratory chain. The molecular mechanism underlying the inability of C. necator H16 to simultaneously utilize carbohydrates and CO2 was identified as the suppression of hydrogenase expression in the presence of fructose. By inducing regulator hoxA to activate hydrogenase expression, an engineered C. necator strain capable of mixotrophic growth was developed. This engineered strain can simultaneously utilize fructose, CO2, and H2, maintain optimal growth, and approach carbon-neutral cultivation. This work provides insights for the mixotrophic cultivation of C. necator and serves as a reference for developing mixotrophic microorganisms in future studies.
    Keywords:  Cupriavidus necator H16; hydrogenase; metabolic engineering; mixotrophy; transcriptomics
    DOI:  https://doi.org/10.1021/acssynbio.5c00802
  53. FASEB J. 2026 Feb 15. 40(3): e71358
    Rosmarinic Acid-Treated Exosomes Modulate TGF-β1/Smad3 Signaling to Alleviate Cardiac Fibrosis in an In Vitro/In Vivo Model.
    Zahra Mansouri, Mahin Dianat, Mohammad Badavi, Ali Asadirad, Nehzat Akiash, Seyyed Ali Mard.
      Cardiac fibrosis (CF) is a major complication of myocardial infarction (MI), impairing myocardial function and leading to heart failure. Rosmarinic acid (RA) exhibits cardioprotective and antifibrotic properties, representing a promising therapeutic strategy for CF. This study evaluated the efficacy of exosomes derived from RA-primed adipose-derived stem cells (ADSCs), focusing on how RA-priming enhances their antioxidant and antifibrotic capacity against CF. An Isoproterenol (ISO)-induced myocardial injury model was established in vitro and in vivo. In vitro, H9C2 cardiomyoblasts were first injured with ISO and then treated with either exosomes (Exo) or RA-primed exosomes (RA-MSC-Exo) to assess cell viability and apoptosis. In vivo, 48 Wistar rats were divided into six groups: Control, Exo, RA-MSC-Exo, ISO, ISO + Exo, and ISO + RA-MSC-Exo. We assessed cardiac biomarkers (CK-MB and troponin I), reactive oxygen species (ROS), and total antioxidant capacity (TAC). We performed echocardiographic, molecular (real-time PCR and Western blotting), and histological analyses (Masson's trichrome staining) to evaluate cardiac function, fibrosis signaling pathways (NF-κB, TGF-β1, SMAD3), and collagen deposition. In vitro, both Exo and RA-MSC-Exo treatments significantly restored cell viability and reduced apoptosis in ISO-injured H9C2 cells. In vivo, both treatments significantly mitigated ISO-induced cardiac injury by reducing cardiac biomarkers, decreasing ROS production, and enhancing TAC levels. These interventions downregulated the expression of NF-κB, TGF-β1, Smad3, and Collagen I, leading to attenuated collagen deposition and improved cardiac function. Our study demonstrates that RA-primed exosomes effectively mitigate CF and improve cardiac function in an ISO-induced myocardial ischemia model. This targeted approach offers a promising therapeutic strategy for managing myocardial injury and its fibrotic complications.
    Keywords:  Rosmarinic acid; SMAD3; TGF‐β1; cardiac fibrosis; exosome
    DOI:  https://doi.org/10.1096/fj.202501842RR
  54. Mater Today Bio. 2025 Dec;35 102271
    Engineered mesenchymal stem cells-laden chondroitin sulfate hydrogel promotes diabetic wound healing through ROS scavenging and macrophage polarization.
    Xi Cao, Ziqi Shen, Xiaohua Wang, Yuanyuan Chu, Runkong Wang, Liyang Zhu, Ruixue Zhong, Zhong Zhang, Mingquan Wu, Xu Zhou, Lei Zhang.
      The treatment of diabetic wound complications has long been a formidable challenge in the clinic, and a multifunctional biomaterial dressing holds great promise as an ideal approach for promoting diabetic wound healing. In this study, we designed a crosslinked chondroitin sulfate (CS) and polyethylene glycol (PEG) hydrogel (CS gel) as a reservoir via a Michael addition reaction. To further enhance the biological functions, surface-engineered mesenchymal stem cells (MSCs) modified with bilirubin-modified chondroitin sulfate-mediated mixed micellar backpacks possessing ROS scavenging/responsive and CD44-targeting abilities (DCMMs) were incorporated into the hydrogel system. The hydrogel served as a physical carrier, providing a sustained-release platform that ensured the long-term presence and controlled delivery of MSCs-tethered micellar backpacks at the wound site. In vitro experiments revealed the remarkable capacity of the hydrogel for ROS scavenging and regulating macrophage polarization. In vivo investigations in diabetic mouse models further confirmed the therapeutic potential, revealing a significant acceleration of wound closure, attenuation of inflammation, and augmentation of angiogenesis. Overall, this innovative hydrogel system that encapsulates surface-engineered mesenchymal stem cells (MSCs-DCMMs) represents a promising remedy and a framework for stem-cell-based therapeutic systems to treat diabetic wounds.
    Keywords:  Diabetic wound healing; Hydrogel; Micellar backpacks; ROS-Responsive; Surface-engineered mesenchymal stem cells
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102271
  55. J Control Release. 2026 Feb 02. pii: S0168-3659(26)00081-7. [Epub ahead of print] 114680
    Large and low-PEG lipid nanoparticles enable efficient dendritic cell targeting for potent mRNA Cancer vaccines.
    Xiaolan Xu, Jiahao An, Dan Bai, Yuanchao Xu, Tingting Wu, Hua Yang, Yueyue Yan, Shaojun Yang, Zifan Wei, Yuchen Yao, Qian Liu, Tao Xu, Lan Zhu.
      Efficient delivery of messenger RNA (mRNA) to dendritic cells (DCs) remains a major challenge limiting the efficacy of mRNA cancer vaccines. Here, we report a large-sized lipid nanoparticle (LLNP) platform specifically engineered for enhanced DC targeting. By reducing PEG-lipid content to 0.3% and proportionally increasing the concentrations of structural lipids and mRNA sixfold relative to the Moderna classic formulation, we generated LLNPs with enlarged size and optimized surface properties that favor DC uptake. Following intravenous administration, LLNPs achieved markedly enhanced mRNA expression in DCs, with ~82% of GFP+ cells identified as DCs and ~ 44% of CD11c+ DCs expressing GFP. LLNPs also promoted DC maturation and antigen presentation. LLNP-mediated delivery of HPV16 E6E7 mRNA elicited robust effector and memory cytotoxic T lymphocyte responses, enabling effective tumor regression at doses as low as 1 μg. Both conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells contributed to antigen presentation, with cDC1 playing the predominant role. Compared with BioNTech's RNA-lipoplex delivery platform, LLNPs demonstrated superior DC transfection, T cell activation, and antitumor efficacy. Collectively, these findings establish LLNPs as a robust and versatile platform for next-generation mRNA cancer vaccines with enhanced therapeutic potential.
    Keywords:  Dendritic cell targeting; Lipid nanoparticles; PEG-lipid content; Size modulation; mRNA cancer vaccine
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114680
  56. Cell Stress. 2026 ;10 9-18
    Antifungal peptides: From modes of action to synergistic and immunologic potential.
    Didac Carmona-Gutierrez, Maria A Bauer, Katharina Kainz, Martin N Odabas, Frank Madeo.
      Fungal infections pose a significant global health threat with rising morbidity and mortality rates. However, the repertoire of effective antifungal drugs remains narrow, a challenge that is further exacerbated by the increasing emergence of (multi)drug-resistant strains. This underscores the urgent need for novel therapeutic strategies. Among them, antifungal peptides (AFPs) have emerged as a promising alternative. AFPs are small, naturally occurring peptides produced by a wide range of organisms, including plants, animals, fungi, and bacteria, as part of their innate immune defense. In addition, synthetic and semisynthetic variants have also been engineered. We here underscore the potential of AFPs as viable candidates for the development of next-generation antifungal therapies. In particular, we advocate their multimodal advantage that spans beyond standalone activity, including their synergistic and immune-regulatory potential.
    Keywords:  Candida; antimycotics; azoles; drug; immune system; resistance; yeast
    DOI:  https://doi.org/10.15698/cst2026.01.315
  57. Ann Oncol. 2026 Feb 02. pii: S0923-7534(26)00039-6. [Epub ahead of print]
    Progress in Targeting the Untouchables: Emerging Approaches for Hard-to-Drug Cancer Targets.
    N Coleman, H Tan, J R Ahnert.
      Innovation in drug development is an evolving concept that can take many forms, and is often confused with iteration, i.e., new versions of existing drug classes targeting familiar oncogenes. Yet meaningful innovation increasingly lies in translating approaches to historically 'untouchable' targets: transcription factors, tumor suppressors, and lineage-defining proteins, which have long resisted conventional pharmacological approaches. At the ESMO Targeted Anticancer Therapies (TAT) 2025 Congress, a growing body of early-phase trials has continued to test and refine this paradigm, showcasing first-in-human studies and novel modalities aimed at drugging long-deemed inaccessible sites. In this manuscript, we review key highlights from ESMO TAT and other pivotal drug development meetings and delve into targeting these so-called 'untouchable' targets. Organized by target class (KRAS, MYC, TP53, WNT) and modality (PROTACs, ADCs, bispecifics), we explore how translational frameworks, rational trial design, and platform-specific engineering are reshaping what is now clinically feasible in drug development. Finally, we present early-phase data from the most compelling trials and compounds and explore what remains to be achieved to move beyond proof-of-concept into clinically meaningful benefits for patients with cancer.
    Keywords:  Protein degradation; Undruggable targets; early-phase clinical trials; targeted therapy; translational oncology
    DOI:  https://doi.org/10.1016/j.annonc.2026.01.012
  58. Small. 2026 Jan 31. e12099
    Extreme-Environment Adaptive Hydrogel with Vagus Nerve Modulation for Diabetic Wound Healing and Emotion Management.
    Yue Hou, Xiaochuan Guo, Xinyi Wang, Yuanfeng Wang, Wei Zhang, Jinhui Ran, Dejia Xu, Yiming Zhang, Yanan Jiang, Feng Lin, Xiangrong Chang, Xiong Lu, Chaoming Xie.
      Chronic diabetic wounds, characterized by persistent inflammation and immune dysregulation, present a significant healing challenge. While traditional hydrogels aid tissue repair, their functionality is often compromised at low temperatures. Herein, we report a polyphenol-mediated conductive hydrogel that remains stable and functional at -80°C. Engineered from casein, dopamine-modified poly(3,4-ethylenedioxythiophene), and a synergistic antifreeze system (dopamine, gluten, glycerol), the hydrogel maintains its conductivity, bioactivity, and therapeutic efficacy after freezing. The hydrogel functions both as a therapeutic dressing and a bioelectronic interface. When coupled with vagus nerve stimulation (VNS), the hydrogel synergistically accelerates full-thickness wound healing by regulating inflammation, scavenging ROS, promoting macrophage M2 polarization, and enhancing angiogenesis. Its remarkable cryo-stability is attributed to polyphenol-mediated water confinement and cryoprotective gluten micelles. Concurrently, the hydrogel facilitates real-time ECG, EMG, and EEG monitoring and enables VNS-driven modulation of EEG-α waves to alleviate depressive-like behavior. This integrated system presents a novel therapeutic paradigm for managing both the physiological and psychological complications of diabetes, even under extreme environmental conditions.
    Keywords:  antifreeze conductive hydrogel; depression alleviation; diabetic wound healing; inflammatory modulation; vagus nerve stimulation
    DOI:  https://doi.org/10.1002/smll.202512099
  59. EMBO J. 2026 Feb 06.
    Assessing target genes for homing suppression gene drive.
    Xuejiao Xu, Jialing Fang, Jingheng Chen, Jie Yang, Xiaozhen Yang, Shibo Hou, Weitang Sun, Jackson Champer.
      Gene drives are engineered alleles that bias their own inheritance in offspring, enabling the spread of specific traits throughout a population. Targeting female fertility genes in a gene drive can be an efficient strategy for population suppression. In this study, we investigated nine female fertility genes in Drosophila melanogaster using CRISPR-based homing gene drives. Employing a multiplexed gRNA approach to prevent the formation of functional resistance alleles, we aimed to maintain high drive-conversion efficiency with low fitness costs in female drive-carriers. Drive efficiency was assessed in individual crosses and had varied performance across different target genes. Notably, drives targeting the octopamine β2 receptor (oct) and stall (stl) genes exhibited the highest drive-conversion rates and were further tested in cages. A drive targeting stl successfully suppressed a cage population with a high release frequency, though suppression failed in another replicate cage with a lower initial release frequency. Fitness costs in female drive carriers were observed in test cages, impacting the overall efficiency of population suppression. Further tests on the fertility of these lines using individual crosses indicated that some fitness costs were due to maternal deposition of Cas9 combined with new gRNA expression, which would only occur in progeny of drive males when testing split drives with separate Cas9 (when mimicking cages with complete drives) but not for complete drive systems. This could enable success in complete drives with higher maternal Cas9 deposition, even if cage experiments in split drives fail. Overall, our findings identify oct and stl as promising fertility targets and demonstrate both the potential and the constraints of fertility-based suppression drives, providing empirical evidence to guide the design and assessment of more efficient population control strategies.
    Keywords:  CRISPR; Female Fertility; Fitness Costs; Homing Gene Drive; Population Suppression
    DOI:  https://doi.org/10.1038/s44318-025-00683-y
  60. Geroscience. 2026 Feb 04.
    Extracellular exosome signature links hypertension and Alzheimer's disease.
    Joakim A Bastrup, Jonas Folke, Sanne S Kaalund, Michel Rasmussen, Susana Aznar, Thomas Jepps.
      Untreated hypertension is a risk factor for late-onset Alzheimer's disease (AD); however, this association is not well understood. The aim of this study was to reveal protein signatures that bridge the pathophysiological changes in hypertension to AD. Using untargeted proteomics, we analyzed brain samples from aged (30- and 40-week-old) spontaneously hypertensive rats (SHRs, n = 12), and age-matched normotensive Wistar Kyoto (WKY, n = 8) controls, and human AD patients (Braak stages 4-6) (n = 30), cerebral amyloid angiopathy (CAA) (n = 5), non-demented controls (Braak stages 0-3) (n = 37). Differential expression and pathway analyses in SHRs highlighted the 'extracellular exosome' pathway. This pathway also showed significant associations to differentially expressed proteins in AD and CAA patients. Comparison between species identified 24 proteins in SHRs and AD, whose trajectory pattern over the progression of hypertension, aligned with those observed during AD Braak stage progression, compared to respective controls. The proteins were similarly associated with extracellular exosomes. Immunostaining and spatial proteomics support vesicle accumulation and dysregulated exosome protein signatures in the cerebrovasculature of both SHR and AD brains. Additionally, the extracellular exosome pathway-association was not identified in a traditional model of familial AD (5xFAD). Our findings demonstrate cross-species translatability between AD and the SHR and provide novel mechanistic insights into a shared dysregulation of cerebral artery-associated exosomes.
    Keywords:  Alzheimer’s disease; Exosomes; Hypertension; Proteomics
    DOI:  https://doi.org/10.1007/s11357-026-02097-y
  61. J Cell Mol Med. 2026 Feb;30(3): e71045
    Targeted Nanodelivery of WGX50 and Curcumin via Gold Nanoparticles for Alzheimer's Therapy.
    Madeeha Shahzad Lodhi, Muhammad Maisam, Muhammad Tahir Khan, Amina Bibi, Dongqing Wei, Kejie Mou.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood-brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%-90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.
    Keywords:  Alzheimer's disease; WGX50; curcumin; gold nanoparticles; insulin; miRNA‐146a‐5p; targeted drug delivery
    DOI:  https://doi.org/10.1111/jcmm.71045
  62. Biotechnol Adv. 2026 Feb 02. pii: S0734-9750(26)00024-8. [Epub ahead of print]88 108818
    Modulation of Clostridioides difficile virulence by metabolites derived from probiotic consortia and genetically edited strains.
    Luana Macedo Nogueira, Eduardo César Meurer, Marcos Pileggi.
      Clostridioides difficile infection (CDI) continues to pose a significant clinical and biotechnological challenge, primarily driven by antimicrobial resistance and frequent recurrence. Emerging strategies are shifting the therapeutic focus from pathobiont eradication to virulence suppression, achieved by targeting the key metabolic and regulatory networks that underpin C. difficile pathogenicity in the gut. This review synthesizes multi-omic data demonstrating that a synergistic approach-restoring secondary bile acid metabolism (through the bai operon), boosting short-chain fatty acid (SCFA) production, and disrupting quorum-sensing systems (e.g., luxS, agr)-can collectively suppress toxin expression, biofilm formation, and spore germination. We further examine how synthetic biology and metabolic engineering are paving the way for next-generation solutions, including engineered probiotics, designer microbial consortia, and live biotherapeutic products endowed with programmable quorum quenching capabilities and optimized metabolic outputs. The integration of genomics, transcriptomics, proteomics, and metabolomics, with computational modeling, now enables the predictive design and industrially scalable production of these microbiome-based interventions. Together, these advances mark a pivotal transition from empirical probiotic use to the era of precision, mechanism-driven microbiome therapeutics designed to achieve durable control of CDI recurrence.
    Keywords:  Gut microbiota; Metabolic engineering; Omic approaches; Quorum sensing; Synthetic biology
    DOI:  https://doi.org/10.1016/j.biotechadv.2026.108818
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