bims-engexo 2026-06-21 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–06–21
sixty-one papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Exosome-mediated cell-cell communication: a new perspective on the mechanisms and therapeutic potential of diabetic microvascular complications.
Exosome engineering and molecular tools for targeted therapy of brain-infecting pathogens: delivery systems, signaling pathways, and therapeutic applications.
Galactose-functionalized engineered outer membrane vesicles for targeted delivery of enterocin Gr17 ameliorate Salmonella Typhimurium-induced colitis.
Exosomes as Biomimetic Nanoplatforms for Synergistic Targeted Chemotherapy and Photothermal Treatment of Breast Cancer.
Serum FAP⁺ exosome-based flow cytometric detection: potential utility in early diagnosis, disease progression assessment, and surgical response monitoring of lung adenocarcinoma.
A safe and anti-inflammatory plant-derived nanovesicle platform for targeted delivery in acute lung injury.
Genetically engineered outer membrane vesicles as next-generation bionanomaterials for therapeutic and diagnostic applications.
Role of LDHA in senescent fibroblast exosomes promoting ferroptosis via histone lactylation-mediated ACSL4 regulation in skin photoaging.
Microfluidic methacrylated hyaluronic acid microspheres incorporating MnO2 and exosomes for antioxidant defense and inflammation regulation in osteoarthritis.
Nanomaterials for Subcellular Organelle Targeting: Unlocking New Avenues for Enhanced Therapeutic Effectiveness.
Dual-engineered small extracellular vesicles targeted delivery miR-126 for reducing age-related bone loss.
Advances in nano-TCM for Alzheimer's disease: lipid-based carriers integrated with innovative delivery strategies.
Cross-species hybrid vesicles enable synergistic immunochemotherapy through enhanced targeted drug delivery and immune activation.
Engineered biomimetic exosomes for small activating RNA delivery: Low-density lipoprotein receptor-related protein-1 targeted blood-brain barrier penetration and dual therapy in intracerebral Hemorrhage.
Engineered Exosomal miR-146a-5p Reprograms BMSC Fate and Restores Mitochondrial Homeostasis in Glucocorticoid-Induced Osteonecrosis of Femoral Head.
Carrier-free targeted co-assembly of glycyrrhizin and puerarin overcomes ocular barriers for corneal alkali burn therapy via macrophage reprogramming.
An Engineered Core-Satellite Magnetic Aptasensor with Built-In Calibration and Regeneration for Accurate Quantification of Oral Cancer Exosomes.
Recent progress of plant-derived extracellular vesicle-like nanoparticles integrated with biomaterials for skin repair.
Engineered bone-targeting Lycium barbarum L.-derived extracellular vesicle-like nanoparticles deliver miR167a-5p to regulate mitochondrial dynamics and metabolic reprogramming in alleviating osteoporosis.
Characterizing the Fate of Anti-CS1 Nanobody Displaying Extracellular Vesicles in Multiple Myeloma.
Vitamin A-coupled MSCs- derived extracellular vesicles relieve acute liver injury by targeting hepatic stellate cells to deliver REDD1.
Engineered Nestin+ TSPC-Derived Exosomes Promote Tendon Repair Via Metabolic Reprogramming.
Engineered small extracellular vesicles in hematologic malignancies: mechanisms, therapeutic strategies, and translational challenges.
A combinatorial therapeutic platform based on graphene-collagen cryogel and apoptotic vesicles for modulating hypertrophic scars.
Regenerative and molecular therapies for myocardial repair (Review).
Extracellular vesicles in solid tumors: from tumor ecology to engineered therapeutics.
Enhancing the regenerative potential of MSC-derived exosomes via 3D microenvironment modulation for cartilage repair.
Dual-targeting macrophage membrane nanosystem enhances radiotherapy-induced antitumor immunity via synergistic nuclear and mitochondrial DNA damage.
Exosomal microRNAs in Periodontitis: From Molecular Footprints to Clinical Frontiers.
In situ macrophage CAR programming via ROS-responsive microneedles enhances efferocytosis and promotes mucosal regeneration.
ROS-responsive bio-hybrid probiotics for synergistic acute lung injury therapy.
A Polydopamine-coated Engineered Type II Collagen Scaffold for Motor Neuron Organization and Spinal Cord Injury Regeneration.
Evaluation of the combination of chitosan hydrogel crosslinker and dental pulp stem cell-derived exosomes on osteoblast viability and differentiation.
Biomimetic fusion nanosystem from ginger exosomes and tumor cell membranes: boosting PLK1-targeted therapy in BRCA-heterogeneous HGSOC.
Electroacupuncture alleviates myocardial ischemia-reperfusion injury by targeting and inhibiting NLRP3 inflammasome-mediated cardiomyocyte pyroptosis via serum exosomal miR-22-3p.
Signaling pathway mechanisms in pancreatic ductal adenocarcinoma tumor microenvironment and emerging targeting strategies for improved prognosis.
Metabolic engineering of Saccharomyces cerevisiae sphingolipid pathways for enhanced phytoceramide production.
IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma.
IL-6R-CD3-engineered regulatory T cells alleviate neuropathic pain by remodeling the neuroimmune microenvironment.
Nanotherapeutic Interventions in Diabetic Wound Healing: Biomarker- Guided Mechanisms and Translational Prospects.
Hyaluronic acid-coated metal-organic framework for co-delivery of Sirtuin 3 gene and zinc to inhibit liver fibrosis.
Extracellular Vesicles and Their Multifaceted Roles in Cancer: Current Evidence from a Narrative Review.
Lipid nanoparticles and extracellular vesicles: emerging cell free therapeutic platforms for hepatobiliary cancers.
Engineered OMVs of Salmonella displaying PlpE antigen provide effective protection against Pasteurella multocida infection in mice.
Molecularly engineered BODIPY photosensitizers for combined cancer phototherapy and immunotherapy.
Astrocyte-derived exosome-mediated siRNA delivery combined with quercetin-Mn complex promotes neural repair in spinal cord injury.
Transplantation of encapsulated fecal microbiota: research progress and future trends.
The miR-212-3p/transferrin axis promotes bone regeneration by modulating iron homeostasis through Schwann cell Exosome-BMSCs communication.
Bioengineered titanium implants functionalized with aptamer-valproic acid conjugates orchestrate macrophage programming and mesenchymal stem cell homing for improved osseointegration.
Exosomal LINC01106 From PRP-Treated ADSCs Alleviates Chondrocyte Inflammatory Injury by Sponging miR-34a-5p to Upregulate SIRT1 Expression.
Reduced Hypotonic Exposure and Sequential Membrane Cholesterol Enrichment Limit Phosphatidylserine Externalization and Enhance Circulatory Retention of Erythrocyte-Derived Microparticles.
Evaluation of Biosynthesized Berberis vulgaris-loaded gold nanocomposites: in vitro cytotoxicity and anti-giardial efficacy against giardia intestinalis.
Progresses of transposon research in Saccharomyces cerevisiae.
Extracellular vesicle-integrated gelatin sponges enhance angiogenesis and cell migration in wound healing.
Engineered Bacillus subtilis to deliver dsRNA via extracellular vesicles against the H9N2 avian influenza virus.
Alkaline loading of extracellular vesicles produced from human neural stem cell-derived neurospheres enables CNS drug delivery.
A sustained-release sinomenine hydrogel targets microglial ferroptosis via Nrf2-hmox1 activation to alleviate diabetic peripheral neuropathy.
Chimeric antigen receptor technology: an emerging translational immunotherapy in nonneoplastic diseases.
Harnessing serum exosomal snoRNAs: A novel liquid biopsy approach for NSCLC diagnosis.
Emerging trends of multifunctional biomaterial scaffolds for targeted antibacterial therapy and enhanced bone regeneration in osteomyelitis.
The Application of Photodynamics Therapy and Tumor Tracing by IR820-Based Nanoparticles Targeting Cancer Cells.

Front Pharmacol. 2026 ;17 1839895

Exosome-mediated cell-cell communication: a new perspective on the mechanisms and therapeutic potential of diabetic microvascular complications.

Ye-Xin Chen, Yi-Shan Wu, Run-Dong Yu, Yi-Yu Dong, Jin-Xi Zhao, Yao-Fu Zhang.

  Diabetic microvascular complications, including diabetic kidney disease, diabetic retinopathy, and diabetic peripheral neuropathy, are associated with a growing burden and frequently present as comorbidities, posing substantial therapeutic challenges. Exosomes have been identified as key drivers in the pathogenesis of these conditions by mediating cell-cell communication. This review summarizes the biogenesis, cargo sorting, and uptake of exosomes, with emphasis on how these processes are reprogrammed under metabolic stress, converting exosomes from physiological regulators into carriers of pathological signals. A focused analysis is provided on how metabolic stress reshapes exosomal cargo profiles in each complication, leading to the enrichment of specific microRNAs, proteins, and lipids. These pathological exosomes establish aberrant communication networks among renal, retinal, and neural cells, through which inflammatory responses, oxidative stress, apoptosis, and fibrosis are amplified and vascular injury signals are transmitted, forming self-reinforcing pathological cycles. Exosomes also hold significant promise for clinical translation. Exosomes derived from body fluids carry molecules from injured cells and can serve as non-invasive biomarkers for early diagnosis. Exosome-based therapeutic strategies, particularly those involving stem cell-derived exosomes or exosomes modulated by antidiabetic drugs and natural products, offer multi-target approaches for microvascular intervention. Current challenges include elucidating cross-organ communication networks in comorbid conditions, advancing clinical standardization of exosomal biomarkers, and developing engineered exosomes for precision therapy. An exosome-mediated cell-cell communication perspective provides a more integrated framework for understanding diabetic microvascular comorbidities and may inform the development of multi-complication co-targeting strategies.

Keywords:  diabetic kidney disease; diabetic microvascular complications; diabetic peripheral neuropathy; diabetic retinopathy; exosomes

DOI:  https://doi.org/10.3389/fphar.2026.1839895
J Nanobiotechnology. 2026 Jun 17.

Exosome engineering and molecular tools for targeted therapy of brain-infecting pathogens: delivery systems, signaling pathways, and therapeutic applications.

Sarad Pawar Naik Bukke, Naik Bukke, Shatrudhan Prajapati, Chandrashekar Thalluri, Shikha Yadav, Ajay Pal Singh, Neha Gupta.

  Brain infections, caused by various pathogens (such as viruses, bacteria, fungi, or parasites), have proven challenging to treat due to limited drug diffusion through the blood-brain barrier and the presence of intracellular reservoirs. As biologically derived nanocarriers, exosomes have emerged as viable candidates for crossing physiological barriers and effectively delivering target molecules into the central nervous system. This review aims to summarize what is currently known about exosome biogenesis, cargo sorting, and immunological function in relation to infectious disease. In addition, it provides information on how different pathogens have taken advantage of exosomal pathways to increase their virulence and modulate the immune response, while also suggesting options for the therapeutic engineering of exosomes. It critically evaluates technological advances made in exosome engineering, such as CRISPR/Cas9-based cargo loading, ligand-directed surface modification of exosomes, targeted delivery of nucleic acids, and creation of stimuli-responsive release systems for exosome cargo for their potential application as precision therapies against pathogens that infect the brain. Pharmacokinetic data and biodistribution studies, along with studies examining how route of administration, inflammatory status, and receptor mediated uptake affect CNS targeting efficacy reflect that exosome engineering offers a novel platform for creating precision therapeutics against pathogens that infect the brain.

Keywords:  Blood brain barrier transport; CNS infections; CRISPR therapeutics; Exosome engineering; Exosomes; Neuroinflammation; Pathogen-derived vesicles; Targeted delivery

DOI:  https://doi.org/10.1186/s12951-026-04683-w
Int J Biol Macromol. 2026 Jun 15. pii: S0141-8130(26)02967-3. [Epub ahead of print]371 153040

Galactose-functionalized engineered outer membrane vesicles for targeted delivery of enterocin Gr17 ameliorate Salmonella Typhimurium-induced colitis.

Kaisheng Shen, Wenyu Ma, Linyue Shi, Tianqi Guo, Yue Wang, Yanbo Wang, Guorong Liu.

  Bacteriocins, antimicrobial peptides from lactic acid bacteria (LAB), represent promising agents against Salmonella Typhimurium-induced colitis. However, their proteinaceous nature leads to poor bioavailability and insufficient concentrations at infection sites, which significantly limits their application potential. Enterocin Gr17 exhibits potent antibacterial activity against S. typhimurium and effectively ameliorates pathogen-induced intestinal barrier damage. Herein, we innovatively developed a targeted oral delivery system termed OMV-Gr17/Gal, based on galactose (Gal)-modified engineered bacterial outer membrane vesicles (OMVs) that expressed and encapsulated enterocin Gr17 (14.2 kDa), with a yield of up to 159.2 μg per mg of OMVs protein, for effective alleviation of S. typhimurium-induced colitis. The lipid bilayer of OMVs protected enterocin Gr17 from gastrointestinal degradation, enhancing the antibacterial efficacy by over 3.4-fold. Moreover, galactose modification further enhanced its cellular uptake efficiency and enabled targeted delivery of enterocin Gr17 to intestinal inflammatory macrophages, thereby exerting superior antioxidant and anti-inflammatory effects. Following oral administration, OMV-Gr17/Gal showed great biocompatibility and prolonged intestinal retention, effectively alleviating the colitis symptoms. Mechanistically, OMV-Gr17/Gal conferred superior anti-colitis efficacy compared to enterocin Gr17 by enhancing the elimination of S. typhimurium from organs, strengthening intestinal barrier function through increased mucus secretion and tight junction expression, suppressing inflammatory responses via MAPK/NF-κB inhibition and T helper 17/regulatory T cells (Th17/Treg) balance restoration, and more effectively remodeling the gut microbiota with elevated short-chain fatty acids (SCFAs) production. This study highlights the significant potential of engineered OMVs to improve the oral bioavailability of bacteriocins and provides new insights into ameliorating S. typhimurium-induced colitis.

Keywords:  Bacteriocin; Inflammatory response regulation; Oral targeted delivery; Outer membrane vesicle; S. typhimurium-induced colitis

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153040
J Biochem Mol Toxicol. 2026 Jun;40(6): e70971

Exosomes as Biomimetic Nanoplatforms for Synergistic Targeted Chemotherapy and Photothermal Treatment of Breast Cancer.

Harsha Sanil, Valliyodu Revathi, Sufina Sudhina, Chandana Yesudas, Areej Nazarudeen, Usha Vijayamoorthy Aswathy, Nalinakshan Abhirami, Akash Chandran, Prasannakumar Sreeja Athul, Diya Maria Siril, Chaithanya Yesudas, A Radhika, Muthunayagam Vibin, Janeesh Plakkal Ayyappan.

  Breast cancer remains the most common cancer in women worldwide, with approximately 2.3 million new cases and 685,000 deaths annually (WHO, 2024). Triple-negative breast cancer (TNBC), the most aggressive subtype, has < 15% 5-year survival in metastatic cases, while conventional therapies are hampered by off-target toxicity, multidrug resistance, and poor tumor accumulation (< 0.7% injected dose per gram of tumor (ID/g)). We present engineered exosomes as next-generation Trojan horses for TNBC: NIR-activatable photothermal agents (polydopamine, BPQDs, or ICG) are integrated into the membrane and chemotherapeutics or nucleic acids (doxorubicin, paclitaxel, siKRAS, siPD-L1, miR-145) encapsulated in the lumen. This "smart" platform exploits exosomes' natural tumor-homing and immune-evasive properties; a single low-power 808 nm laser pulse triggers mild hyperthermia (42°C-45°C), immunogenic cell death, and burst payload release, converting "cold" TNBC into "hot" tumors. In orthotopic and metastatic 4T1/MDA-MB-231 models, one intravenous dose plus 5-min irradiation achieved a substantial tumor reduction in preclinical models, significant metastasis inhibition in murine models, long-term memory immunity, and 15%-18% IDg tumor accumulation with negligible toxicity. Major challenges-donor heterogeneity, low yields, rapid clearance, regulatory gaps, and limited NIR-II probes-are being overcome via single-cell omics, advanced bioreactors, CD47/PEGylation engineering, rigorous CMC standards, and PbS quantum dot loading. Future directions include AI/CRISPR-optimized design, NIR-II platforms, checkpoint inhibitor synergy, with early-stage clinical translation of photothermal and immunomodulatory exosome-based therapeutics currently underway, highlighting their potential to advance precision oncology. "However, challenges including scalability, batch variability, and regulatory standardization remain significant barriers to clinical translation."

Keywords:  breast cancer; exosomes; hybrid nanocarriers; nanodrug delivery; photothermal therapy; tumor targeting

DOI:  https://doi.org/10.1002/jbt.70971
J Nanobiotechnology. 2026 Jun 19.

Serum FAP⁺ exosome-based flow cytometric detection: potential utility in early diagnosis, disease progression assessment, and surgical response monitoring of lung adenocarcinoma.

Ming Liu, Xiamin He, Jing Chen, Juan Huang, Xiang Lv, Guanghua Liu, Yijing Cai, Yanhui Lin, Yaocheng Wang, Yingying Cao, Minjian Huang, Rongzhao Zhang, Lilan Zhao, Jianlin Chen, Chundong Yu, Hao Zhang, Fangqin Xue, Yi Huang.

   BACKGROUND: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, and currently available serum biomarkers have limited sensitivity and specificity for early diagnosis. We investigated whether serum fibroblast activation protein-positive (FAP⁺) exosomes could serve as a minimally invasive biomarker for LUAD.
METHODS: We examined FAP expression and exosomal localization in cancer-associated fibroblasts (CAFs), evaluated a magnetic bead-based strategy for enriching FAP⁺ exosomes, and established a latex bead-based flow cytometric assay using biotinylated anti-FAP antibody and streptavidin-PE detection. The assay was then evaluated in healthy donors (HD), patients with benign lung lesions (LBL), and patients with LUAD, and its diagnostic performance was compared with conventional serum biomarkers, including CEA, NSE, and CYFRA21-1.
RESULTS: Exosomes released by CAFs showed elevated FAP expression, and FAP was associated with the exosomal marker CD9, supporting a possible CD9-associated exosomal sorting mechanism. In the clinical cohort, serum FAP⁺ exosome levels were significantly higher in LUAD than in HD and LBL, and increased with disease stage. In early-stage LUAD, serum FAP⁺ exosomes showed favorable diagnostic performance, with an AUC of 0.932, 88.4% sensitivity, and 87.6% specificity. Compared with conventional serum biomarkers, including CEA, NSE, and CYFRA21-1, serum FAP⁺ exosomes showed superior diagnostic performance in this cohort, while combined biomarker models provided only modest incremental improvement over FAP⁺ exosomes alone. Serum FAP⁺ exosome levels also decreased significantly after surgery, suggesting that this marker may reflect early postoperative changes.
CONCLUSION: This study provides evidence that FAP is enriched in exosomes released by CAFs and may be incorporated into exosomes through a CD9-associated mechanism. We further established a serum FAP⁺ exosome-based flow cytometric assay that may serve as a promising minimally invasive strategy for LUAD diagnosis, disease progression assessment, and early postoperative monitoring.

Keywords:  Cancer-associated fibroblasts; Exosomes; Fibroblast activation protein; Liquid biopsy; Lung adenocarcinoma

DOI:  https://doi.org/10.1186/s12951-026-04695-6
Bioact Mater. 2026 Aug;62 587-606

A safe and anti-inflammatory plant-derived nanovesicle platform for targeted delivery in acute lung injury.

Xianhao Wu, Hanqing Li, Huizhen Fan, Anyi Wu, Yingying Ma, Li Wei, Yun Wang, Yanfei Mao, Min Lu, Lai Jiang.

  Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening pulmonary disorders with extremely high mortality rates, for which effective and safe therapeutic strategies remain limited. The development of targeted and biocompatible drug delivery systems is urgently needed to control pulmonary inflammatory cascades while minimizing systemic toxicity. Plant-derived extracellular vesicles offer a naturally safe and anti-inflammatory platform for therapeutic delivery. Ginsenoside Rb1 (GRb1), a major bioactive compound from ginseng, possesses potent anti-inflammatory and anti-apoptotic properties, whereas lemon-derived EVs (LEVs) exhibit intrinsic antioxidant and anti-inflammatory effects. Here, we engineered a multifunctional, biocompatible drug delivery platform, GRb1@LEVs-cRGD, in which ginsenoside Rb1 is incorporated into and fused with LEVs to form hybrid bio-nanovesicles, while the vesicle surface is functionalized with cyclic RGD (cRGD) peptides to target integrin αvβ3 highly expressed in inflamed pulmonary tissues, thereby enhancing site-specific delivery. In vitro and in vivo studies confirmed that GRb1@LEVs-cRGD effectively inhibited M1 macrophage polarization, suppressed inflammatory cascades, and preserved epithelial-endothelial integrity. Furthermore, exogenous cholesterol loading improved vesicle stability, maintained the pH gradient, and enhanced the loading efficiency of tigecycline and vancomycin by six-fold. In murine models of bacterial pneumonia induced by carbapenem-resistant Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus, antibiotic-loaded GRb1@LEVs-cRGD efficiently accumulated at infection sites and exhibited synergistic anti-inflammatory and bactericidal effects. Overall, this study demonstrates that GRb1@LEVs-cRGD is a safe, targeted, and multifunctional therapeutic platform with significant potential for ALI/ARDS treatment.

Keywords:  Acute lung injury; Drug delivery platform; Ginsenoside Rb1; Lemon‐derived extracellular vesicles; Macrophage

DOI:  https://doi.org/10.1016/j.bioactmat.2026.03.033
J Mater Chem B. 2026 Jun 04.

Genetically engineered outer membrane vesicles as next-generation bionanomaterials for therapeutic and diagnostic applications.

Xuyu Bian, Ziyan Huang, Chenhang Xu, Jiawei Yue, Yumin Wu.

Outer membrane vesicles (OMVs), naturally released by Gram-negative bacteria, represent a unique class of bionanomaterials with inherent immunogenicity, efficient cellular delivery, and scalable production. However, their native toxicity, compositional heterogeneity, and lack of targeting specificity have hindered broader therapeutic translation. Advances in genetic engineering and synthetic biology have revolutionized OMV design, transforming these biological byproducts into highly programmable bionanomaterial platforms. This review systematically outlines the key engineering strategies for OMVs, including surface display for targeting and immunomodulation, cargo loading for encapsulating nucleic acids, proteins, and drugs, and membrane modulation for tuning stability and safety. We highlight the transformative applications of genetically engineered OMVs (geOMVs) in cancer immunotherapy, next-generation vaccines, targeted delivery, and diagnostic imaging. Finally, we discuss the critical challenges in the clinical translation-such as scalable manufacturing, safety profiling, and regulatory pathways-and propose future directions integrating synthetic biology, materials science, and artificial intelligence to realize the full potential of geOMVs as intelligent, precision therapeutic and diagnostic platforms.

DOI: https://doi.org/10.1039/d6tb00650g
Epigenetics Chromatin. 2026 Jun 14.

Role of LDHA in senescent fibroblast exosomes promoting ferroptosis via histone lactylation-mediated ACSL4 regulation in skin photoaging.

Tingting Yan, Lixia Huang, Jingjing Tao, Yunling Yan, Yiping Zhong, Xuebiao Peng.

   OBJECTIVE: This study aimed to elucidate the mechanism of Lactate Dehydrogenase A (LDHA) in senescent fibroblast-derived exosomes during skin photoaging, focusing on the molecular pathway by which it regulates Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) expression through histone lactylation, thereby inducing ferroptosis and accelerating skin photoaging.
METHODS: An ultraviolet B (UVB)-induced senescence model was established using human foreskin fibroblasts. Exosomes were isolated from senescent fibroblasts and characterized. Their features and uptake were assessed using Western blot, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and immunofluorescence. Small interfering RNA was employed to knock down LDHA and ACSL4 gene. Pharmacological inhibitors (FX11, Ferrostatin-1) and sodium lactate rescue experiments were utilized. Lactate levels, histone H3K18 lactylation modification, ACSL4 transcriptional activity, and ferroptosis markers were detected to assess the effects of ACSL4 gene lactylation on ferroptosis. The biological effects of exosomal LDHA in photoaged tissue were validated using an in vivo UVB-irradiated mouse model.
RESULTS: UVB irradiation induced fibroblast senescence and significantly upregulated LDHA expression. Exosomes from senescent fibroblasts were effectively taken up by HaCaT cells, leading to increased lactate levels and enhanced histone H3K18 lactylation in recipient cells. LDHA knockdown or inhibition downregulated ACSL4 expression and suppressed ferroptosis, whereas exogenous lactate partially restored these effects. RNA sequencing and ChIP-qPCR results indicated that LDHA-mediated lactylation modification was enriched at the ACSL4 promoter region, enhancing its transcriptional activity. In vivo experiments further confirmed that senescent exosomes accelerated UVB-induced skin collagen degradation and ferroptosis, while LDHA intervention significantly alleviated photoaging damage.
CONCLUSION: Senescent fibroblast-derived exosomes deliver LDHA, promoting histone lactylation modification, which upregulates ACSL4 expression and activates the ferroptosis pathway, ultimately accelerating skin photoaging. This study reveals the coupling mechanism between metabolic signaling and epigenetic regulation in skin aging, providing new molecular targets and a theoretical basis for anti-photoaging therapy.

Keywords:  ACSL4; Exosomes; Ferroptosis; Histone lactylation; Lactate dehydrogenase A (LDHA); Skin photoaging

DOI:  https://doi.org/10.1186/s13072-026-00683-0
Mater Today Bio. 2026 Jun;38 103300

Microfluidic methacrylated hyaluronic acid microspheres incorporating MnO2 and exosomes for antioxidant defense and inflammation regulation in osteoarthritis.

Jianxiang Teng, Jiazhao Pan, Pengcheng Yan, Tianqi Zhou, Zihao Zou, Xiaolin Shu, Hao Liu, Zhuoran Zhang, Sheng Zhou, Qiuhan Chen, Dandan Shen, Xing Zhao, Xiaobin Tian, Long Yang.

  Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degeneration, chronic inflammation, and oxidative stress-induced mitochondrial dysfunction. Herein, we engineered an integrated therapeutic platform by encapsulating mesenchymal stem cell-derived exosomes (Exo) and manganese dioxide (MnO2) nanozymes into methacrylated hyaluronic acid (HAMA) hydrogel microspheres (HAMA-Exo-MnO2) via microfluidic fabrication. Systematic in vitro and in vivo evaluations assessed the microspheres' anti-inflammatory, antioxidant, and chondrogenic regenerative properties. In vitro experiments demonstrated that HAMA-Exo-MnO2 microspheres effectively attenuated OA-like pathological changes in chondrocytes, remodeled the inflammatory microenvironment, and scavenged reactive oxygen species (ROS). In a rat OA model induced by destabilization of the medial meniscus (DMM), intra-articular injection of HAMA-Exo-MnO2 microspheres ameliorated disease progression, enhanced articular cartilage regeneration, and restored joint function. Transcriptomic sequencing and subsequent validation in cocultured OA chondrocytes revealed significant upregulation of ALDH3A1, which mitigated oxidative stress, activated the NRF2 signaling axis, promoted downstream antioxidant gene expression, and restored mitochondrial electron transport chain activity. In summary, this study highlights that the engineered HAMA hydrogel microspheres provide a multifunctional therapeutic strategy for OA treatment, integrating immune microenvironment modulation, cartilage regeneration, and antioxidant protection.

Keywords:  Exosomes; Methacrylated hyaluronic acid; Microfluidics; Mitochondrial function; Nanozyme; Osteoarthritis

DOI:  https://doi.org/10.1016/j.mtbio.2026.103300
J Drug Target. 2026 Jun 17. 1-51

Nanomaterials for Subcellular Organelle Targeting: Unlocking New Avenues for Enhanced Therapeutic Effectiveness.

Kiarash Solouki, Muhammad Sohail.

  Subcellular organelle targeting is changing the way nanomedicine is designed, moving the field beyond simple cellular entry toward more precise intracellular localization, controlled cargo release, and functional activity within disease-relevant compartments. This review critically discusses nanomaterial-based strategies for targeting the nucleus, mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus, and cytoskeleton-associated trafficking pathways. Its main novelty is the use of a cross-organelle, mechanism-based framework that links nanocarrier physicochemical properties with intracellular transport biology, rather than examining each organelle or delivery platform separately. Lipid nanoparticles, polymeric carriers, dendrimers, inorganic nanomaterials, biomimetic systems, and engineered extracellular vesicles are compared according to their targeting mechanisms, cargo compatibility, therapeutic potential, and translational limitations. Particular attention is given to nuclear import mediated by NLS-, CPP/TAT-, and aptamer-based strategies; mitochondrial delivery shaped by membrane potential, membrane fusion, and redox-responsive release; lysosomal targeting for pH- and enzyme-activated therapies; and ER/Golgi-directed delivery through retrograde trafficking, retention motifs, and modulation of stress-related pathways. The review also brings together several emerging directions, including stimuli-responsive release, biomimetic surface engineering, extracellular vesicle scalability, CRISPR/Cas delivery, base and prime editing, and targeted protein degradation, all of which may support more programmable forms of intracellular therapy. Importantly, it separates true organelle localization from transient trafficking or nonspecific perinuclear accumulation, emphasizing the need for stronger and more reliable validation methods. Key barriers remain, including inefficient endosomal escape, off-target intracellular accumulation, organelle-specific toxicity, long-term safety concerns, reproducibility, scalable manufacturing, and regulatory classification. Overall, this review frames organelle-directed nanomedicine as a rational design strategy for improving therapeutic precision, while also stressing that clinical translation will depend on clear evidence of durable, safe, and measurable therapeutic benefit at the organelle level.

Keywords:  Subcellular organelle targeting; intracellular trafficking; organelle-directed nanomedicine; stimuli-responsive nanocarriers; translational nanomedicine

DOI:  https://doi.org/10.1080/1061186X.2026.2691784
Biomed Mater. 2026 Jun 17.

Dual-engineered small extracellular vesicles targeted delivery miR-126 for reducing age-related bone loss.

Junming Tao, Ruiyu Du, Yi Zhang, Mengru Hong, Shaochen Duan, Datian Fu, Yue Chen, Chao Liang, Wei Jing.

  MiRNA based nucleic acid therapeutics have been extensively investigated for the treatment of agerelated diseases. However, efficient delivery of miRNA and effective therapy for age-related bone loss remain major challenges. In this study, we devised an engineered small extracellular vesicle (sEV) platform to address the dysregulation of bone homeostasis in the elderly. Initially, miR-126 was encapsulated into sEV to generate miR-126 loaded small extracellular vesicles (m-sEV), whose capacity to enhance vascularized bone regeneration was validated in vitro and in a mandibular defect model of aged rats. To further optimize systemic therapeutic efficacy, we functionalized m-sEV with a bone-targeting peptide:(DSS) 6 , thereby constructing bone-targeting engineered vesicles (Bm-sEV). Systemic administration of Bm-sEV enabled precise miR-126 targeted delivery to bone tissue, resulting in increased abundance of type H vessels in the femur, improved bone microarchitecture, and attenuation of age-related bone loss. Mechanistic analyses demonstrated that the angiogenesisosteogenesis coupling effect was mediated by upregulation of endothelial Integrin β3 (ITGB3), which subsequently activated the ITGB3/ERK2 signaling cascade. Notably, Bm-sEV also restored the profoundly impaired osteoclastic activity in aged femurs, thereby re-establishing skeletal homeostasis. Collectively, Our study provides a promising approach for the treatment of age-related bone loss by combining biological macromolecules such as (DSS) 6 and miR-126 with sEV.

Keywords:  Angiogenesis-Osteogenesis coupling. Graphical; Engineered small extracellular vesicles; Targeting drug delivery

DOI:  https://doi.org/10.1088/1748-605X/ae7ee3
J Nanobiotechnology. 2026 Jun 15.

Advances in nano-TCM for Alzheimer's disease: lipid-based carriers integrated with innovative delivery strategies.

LiLi Deng, Huan Li, ShaSha Yang, FengMing Chen, JiaXin Qiao, HuiZhong Bao, XiaoMeng Wang, ShiChao Fang, Bing Xu, ZhiShu Tang.

  Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by β-amyloid (Aβ) plaque deposition, tau hyperphosphorylation, neuroinflammation, and oxidative stress. However, current therapies remain largely symptomatic. Traditional Chinese Medicine (TCM)-derived monomers exhibit considerable anti-AD potential owing to their multitarget neuroprotective activities. However, their therapeutic translation is severely limited by poor stability, low bioavailability, and restricted brain delivery across the blood-brain barrier (BBB). This review summarizes the pathological basis of AD, the neuroprotective mechanisms of representative TCM-derived monomers, and the major BBB-related barriers that hinder effective brain delivery. Particular emphasis is placed on lipid-based nanocarriers, including exosomes, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), as platforms for improving drug stability, BBB transport, and brain accumulation. We further highlight innovative delivery strategies that integrate ligand-mediated targeting with biomimetic modification, particularly cell membrane camouflage and exosome-inspired engineering. These approaches may confer immune evasion, prolonged circulation, enhanced biocompatibility, and improved lesion-oriented delivery. Finally, we discuss the challenges facing the clinical translation of lipid-based nanocarriers, including large-scale production, quality control, regulatory considerations, and long-term safety. Collectively, these lipid-based nanoplatforms provide a promising framework for advancing next-generation nano-TCM therapeutics for AD. Future progress will depend on optimized carrier design, rigorous mechanistic validation, comprehensive long-term safety assessment, and clinically relevant translational studies.

Keywords:  Alzheimer’s disease; Biomimetic modification; Blood-brain barrier; Ligand functionalization; Lipid-based nanocarriers; Traditional Chinese Medicine-derived monomers

DOI:  https://doi.org/10.1186/s12951-026-04654-1
J Nanobiotechnology. 2026 Jun 19.

Cross-species hybrid vesicles enable synergistic immunochemotherapy through enhanced targeted drug delivery and immune activation.

Zhou Fang, Saichao Wei, Shaoqian Wang, Jiaqi Xu, Min Zhang, Mingyu Yin, Jun Wang, Kehai Liu.

  To overcome the critical challenges of insufficient drug targeting and restricted dendritic cell (DC) activation in chemo-immunotherapy, this study developed an innovative cross-species hybrid vesicle delivery system. By fusing extracellular vesicles derived from 4T1 tumor cells (TEV) with kiwifruit-derived extracellular vesicles (KEV), we constructed a homologous targeting hybrid vesicle carrier (TKEV). This platform was co-loaded with chemotherapeutic agent doxorubicin (DOX) and Bcl-2 siRNA (siBcl2) to form a combination therapeutic system (TKDS). Key findings demonstrate: (1) TKDS achieves precise tumor-targeted delivery, significantly enhancing tumor cell apoptosis through combined chemo-gene therapy; (2) The KEV component effectively stimulated DC maturation, enhanced antigen presentation, and increased CD8+ T cell infiltration in tumors; (3) In a 4T1 murine breast cancer models, TKDS significantly enhanced antitumor efficacy through synergistic immunochemotherapy. To our knowledge, this work provides the first evidence that a cross-species vesicle fusion strategy can simultaneously enhance drug targeting and immune activation, offering a versatile and promising platform for developing highly effective and safer immunochemotherapy regimens.

Keywords:  Combination therapy; DC maturation; Hybrid vesicles; Immunochemotherapy; Targeting

DOI:  https://doi.org/10.1186/s12951-026-04699-2
J Control Release. 2026 Jun 18. pii: S0168-3659(26)00515-8. [Epub ahead of print]396 115112

Engineered biomimetic exosomes for small activating RNA delivery: Low-density lipoprotein receptor-related protein-1 targeted blood-brain barrier penetration and dual therapy in intracerebral Hemorrhage.

Lixing Xu, Yan Song, Huimin Tao, Luyun Ni, Haiqin Huang, Jiabing Shen.

  Efficient brain-targeted gene delivery remains a formidable primary bottleneck in the clinical management of intracerebral hemorrhage (ICH). Herein, we engineered a dual-functional biomimetic nanoplatform (L57-NExos@saRNA) that synergizes active blood-brain barrier (BBB) penetration with intrinsic neuroregeneration. Guided by transcriptomic profiling, a small activating RNA (saRNA) was designed to upregulate activating transcription factor 3 (ATF3) -a critical repressor of the Toll-like receptor 4 (TLR4) neuroinflammatory cascade. To overcome formidable physiological barriers, the saRNA was condensed within neural stem cell-derived exosomes (NExos) surface-functionalized with the low-density lipoprotein receptor-related protein-1 (LRP1)-targeting peptide L57. By proactively exploiting the pathological upregulation of LRP1 on BBB-associated astrocytes following ICH, this L57-modified nanoplatform achieves highly efficient receptor-mediated transcytosis, ensuring robust and specific accumulation at the hemorrhagic lesion. Once internalized, the nanomedicine orchestrates a profound dual-therapeutic response. First, the delivered saRNA specifically reprograms microglia from a neurotoxic (M1) to a neuroprotective (M2) phenotype. This shift fundamentally rectifies maladaptive microglial-astrocyte crosstalk, subsequently driving reactive astrocytes toward an A2 protective state to deeply detoxify the inflammatory microenvironment. Concurrently, the bioactive NExos carrier itself transcends its role as a mere vehicle by activating the PI3K/Akt survival pathway, directly inhibiting neuronal apoptosis and facilitating network repair. By seamlessly converging precise BBB-targeted gene regulation with biomimetic carrier-driven repair, this versatile delivery system presents a highly translational and promising therapeutic paradigm for ICH.

Keywords:  Brain-targeting; LRP1; NExos; Transcytosis; saRNA

DOI:  https://doi.org/10.1016/j.jconrel.2026.115112
Adv Sci (Weinh). 2026 Jun 15. e75897

Engineered Exosomal miR-146a-5p Reprograms BMSC Fate and Restores Mitochondrial Homeostasis in Glucocorticoid-Induced Osteonecrosis of Femoral Head.

Zehui Lv, Xuejie Cai, Yiming Xu, Xingdong Yang, Ruoying Wang, Han Wang, Yixin Bian, Jiawei Xu, Jiao Lu, Lulu Liu, Yingjie Wang, Jibin Song, Bin Feng, Xisheng Weng.

  Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) involves stem cell senescence, mitochondrial dysfunction, and impaired bone regeneration. However, the molecular basis linking GC stress to bone marrow stromal cell (BMSC) dysfunction remains unclear. Here, we identify miR-146a-5p as a key regulator of BMSC fate under GC exposure, through comprehensive transcriptomic analysis of clinical bone marrow samples from GC-induced ONFH patients. Exosomes engineered to deliver miR-146a-5p restored mitochondrial membrane potential, suppressed oxidative stress, and reactivated mitophagy by targeting the TRAF6-NF-κB axis. These exosomes reversed GC-induced senescence and enhanced osteogenic and angiogenic capacity in vitro and in vivo. In a rat ONFH model, intraosseous delivery of miR-146a-5p exosomes improved trabecular structure and vascularization. Single-cell RNA-seq revealed a shift toward osteogenic and immunomodulatory BMSC subtypes. Our findings demonstrate that miR-146a-5p-engineered exosomes rejuvenate skeletal regeneration by restoring mitochondrial homeostasis and inflammatory balance, offering a promising cell-free therapy for GC-associated ONFH.

Keywords:  exosomes; glucocorticoid; miR‐146a‐5p; mitochondrial homeostasis; mitophagy; osteonecrosis of the femoral head; stem cell senescence

DOI:  https://doi.org/10.1002/advs.75897
Mater Today Bio. 2026 Aug;39 103337

Carrier-free targeted co-assembly of glycyrrhizin and puerarin overcomes ocular barriers for corneal alkali burn therapy via macrophage reprogramming.

Hanhan Peng, Haoyu Li, Jianing Lin, Licheng Li, Muyan Li, Hai Huang, Junyong Wu, Baihua Chen.

  Corneal alkali burns (CAB) represent a devastating form of ocular trauma characterized by the rapid penetration of alkaline agents, triggering a destructive cascade of inflammatory infiltration, neovascularization, and fibrotic remodeling that compromises ocular transparency. Current pharmacological interventions are largely palliative and severely hampered by rapid precorneal clearance and poor epithelial penetrability. To overcome these formidable dynamic and static ocular barriers, we engineered a carrier-free, targeted nanoplatform via the spontaneous co-assembly of natural bioactives glycyrrhizin (GA) and puerarin (PUE), surface-functionalized with cyclic arginine-glycine-aspartic acid (GP@cRGD NPs). The GP@cRGD NPs exhibited robust physicochemical stability and rapid release kinetics precisely tailored for acute trauma intervention. Crucially, cRGD modification significantly enhanced precorneal retention and trans-epithelial penetration via integrin-targeted interactions. In vivo evaluations demonstrated that topical administration of GP@cRGD NPs markedly accelerated epithelial regeneration, suppressed pathological neovascularization, and successfully restored corneal optical clarity in a murine CAB model. Mechanistically, in vivo transcriptomic profiling and immunofluorescence corroborated that this nanomedicine synergistically reprogrammed the local immune microenvironment by directly inhibiting M1 macrophage polarization and extinguishing downstream pro-inflammatory and pro-fibrotic signaling cascades. Ultimately, this study demonstrates that our targeted, multi-mechanistic nano-formulation holds substantial promise for clinical translation, emerging as a powerful therapeutic intervention against severe chemical burns of the eye.

Keywords:  Carrier-free nanoparticles; Corneal alkali burns; Corneal neovascularization; Inflammation; Macrophage reprogramming; Targeted delivery

DOI:  https://doi.org/10.1016/j.mtbio.2026.103337
ACS Appl Mater Interfaces. 2026 Jun 18.

An Engineered Core-Satellite Magnetic Aptasensor with Built-In Calibration and Regeneration for Accurate Quantification of Oral Cancer Exosomes.

Wenxi Wang, Renjie Li, Siqi Wei, Wenli Chen, Zhongxu Li, Xiaobo Dai, Bing Yan, Xiandeng Hou, Li Wu.

  Exosomes carry diverse biologically active substances that can be transferred between cells, thereby influencing physiological and pathological states of the organism. Abnormal exosome levels are closely associated with cancer. Consequently, the precise detection of exosomes holds considerable importance for noninvasive cancer diagnosis and monitoring. Nevertheless, achieving highly sensitive and consistently reproducible detection of exosomes continues to pose a significant challenge in clinical diagnostics. In this research, we developed a reusable magnetic aptamer-based surface-enhanced Raman scattering (SERS) sensor with built-in calibration for the accurate quantification of exosomes derived from oral cancer. The sensor was synthesized through a layer-by-layer assembly strategy to form an internal standard encoded core-satellite structure (NiFe2O4@PB@Ag), which was subsequently conjugated with SH-modified complementary DNA (cDNA) to form NiFe2O4@PB@Ag-cDNA. This was then hybridized with ROX-labeled aptamers (ROX: 6-carboxy-X-rhodamine) to construct the final NiFe2O4@PB@Ag-dsDNA SERS aptasensor. Magnetic-induced assembly of the sensor, combined with the surface plasmon effect, significantly improved the SERS performance, enabling dual amplification of both internal standard and target signals. This resulted in a 1.9-fold increase in signal intensity compared to the condition lacking magnetic-induced assembly. Furthermore, this SERS sensor exhibited a wide linear range for exosome detection, spanning from 5.0 × 103 to 5.0 × 1011 particles/mL, with a limit of detection (LOD) as low as 1.15 × 103 particles/mL. Finally, in clinical testing of plasma samples, the sensor reliably differentiated exosome concentrations between individuals with oral cancer and healthy controls, providing a robust and reliable platform for exosome-based liquid biopsy in clinical applications.

Keywords:  NiFe2O4@PB@Ag substrate; exosomes; oral cancer; recyclable detection; self-reporting nanoprobes; surface-enhanced Raman scattering

DOI:  https://doi.org/10.1021/acsami.6c09184
J Nanobiotechnology. 2026 Jun 13.

Recent progress of plant-derived extracellular vesicle-like nanoparticles integrated with biomaterials for skin repair.

Siqi Wu, Yi Zheng, Xiang Lian, Yahong Chen, Chuandong Wang, Peng Xu, Kai Liu.

  The skin, serving as a crucial physical and immunological barrier, faces significant regenerative challenges after injury or dysfunction. Recently, plant-derived extracellular vesicle-like nanoparticles (PELNs) have emerged as a highly potent, cell-free therapeutic strategy for skin tissue engineering, offering rich bioactive components, low immunogenicity, and inherent biocompatibility. However, PELNs face limitations such as poor stability, weak targeting ability, and rapid clearance, hindering their clinical applications. The latest progress in integrating or engineering PELNs with functional biomaterial delivery systems provides a promising strategy to overcome these challenges. This review systematically explores the biological characteristics of PELNs, emphasizing the integration and engineering strategies with advanced biomaterials to enhance their therapeutic effects. Firstly, the synergistic mechanisms of PELN-biomaterial composites across diverse dermatological applications, including wound healing, skin photoaging, and inflammatory skin diseases were reviewed. Secondly, the corresponding mechanisms of immune microenvironment remodeling, angiogenesis, and the restoration of redox homeostasis were also summarized. Finally, the clinical translation and regulatory landscape with challenges and perspectives of PELN-biomaterial composites were analyzed.

Keywords:  Biomaterial-assisted extracellular vesicles; Extracellular vesicle engineering; Nanobiomedical applications; Plant-derived extracellular vesicle-like nanoparticles; Skin repair

DOI:  https://doi.org/10.1186/s12951-026-04678-7
Mater Today Bio. 2026 Jun;38 103312

Engineered bone-targeting Lycium barbarum L.-derived extracellular vesicle-like nanoparticles deliver miR167a-5p to regulate mitochondrial dynamics and metabolic reprogramming in alleviating osteoporosis.

Shuai Chen, Miaochao Qin, Qilong Zhao, Ningsheng Tian, Lingling Yu, Liansheng Shao, Su Yan, Xinyu Ding, Pengfei Sun, Peng Ma, Junwu Wang, Penghua Fang, Wen Min.

  With the exacerbation of global population aging, the development of novel therapeutic strategies for osteoporosis (OP) has emerged as a pressing worldwide challenge. As an emerging natural nanomedicine, medicinal plant-derived extracellular vesicle-like nanoparticles (EVLPs) have shown considerable potential in OP treatment due to their advantages, such as good bioavailability, high biosafety characteristics, and natural targeting. Herein, we isolated Lycium barbarum L.-derived EVLPs (LB-EVLPs) from fresh LB via ultracentrifugation combined with sucrose gradient centrifugation and further functionalized LB-EVLPs with the bone-targeting peptide SDSSD (BT-LB-EVLPs) to treat OP. This engineered LB-EVLPs exhibited selective targeting of bone tissue and were effectively internalized by bone marrow mesenchymal stem cells (BMSCs), with a distinct propensity for mitochondrial localization. In ovariectomized (OVX)-induced osteoporotic mice, BT-LB-EVLPs alleviated bone loss, improved bone microstructure, and enhanced bone strength. Proteomic profiling indicated that BT-LB-EVLPs reprogram mitochondrial metabolism by enhancing oxidative phosphorylation while suppressing excessive glycolytic flux, thereby exerting anti-osteoporotic effects. In vitro experiments demonstrated that BT-LB-EVLPs attenuated oxidative stress, promoted mitochondrial fusion, inhibited mitochondrial fission, and facilitated metabolic reprogramming in BMSCs, ultimately restoring mitochondrial function and enhancing osteogenic differentiation. Through lentiviral-mediated overexpression of SLC25A26 combined with miR167a-5p mimic/inhibitor interventions, we verified that miR167a-5p derived from BT-LB-EVLPs directly targets the mitochondrial transporter gene SLC25A26, thereby regulating mitochondrial dynamics, sustaining energy metabolism balance, and promoting osteoblastogenesis. Additionally, in vivo knockdown of miR167a-5p exacerbated bone loss and bone microstructural damage, and abolished the anti-osteoporosis effect of BT-LB-EVLPs. Collectively, these findings emphasized this engineered LB-EVLPs as a promising targeted nanotherapeutic approach for OP treatment.

Keywords:  Bone-targeting; Extracellular vesicle-like nanoparticles; Osteoporosis; Oxidative phosphorylation; Traditional Chinese medicine

DOI:  https://doi.org/10.1016/j.mtbio.2026.103312
J Extracell Vesicles. 2026 Jun;15(6): e70325

Characterizing the Fate of Anti-CS1 Nanobody Displaying Extracellular Vesicles in Multiple Myeloma.

Michiel De Coster, Lukas Hyka, Sophie De Cock, Sofie Meeussen, Zuowei Wang, Chenggong Tu, Sophie Hernot, Nick Devoogdt, Guido David, Kim De Veirman, Karin Vanderkerken, Eline Menu, Pascale Zimmermann, Elke De Bruyne.

  Extracellular vesicles (EVs) are promising delivery vehicles capable of transporting therapeutic agents across biological barriers. However, native EVs primarily accumulate in liver, spleen and lungs, limiting targeted delivery to disease sites. To enhance their targeting efficiency for the plasma cell cancer multiple myeloma (MM), localized in the bone marrow (BM), we engineered HEK293-derived EVs to display a nanobody (Nb) against the MM cell surface marker CS1. We confirmed enrichment of the Nb construct on engineered EVs and binding of α-CS1 EVs to CS1. In vitro, we found enhanced α-CS1 EV uptake by MM cell cultures. In vivo, we first compared the biodistribution of HEK293-derived native EVs in healthy and MM-bearing mice. Although native EVs reached the BM in both groups, MM-bearing mice showed increased liver and lung accumulation together with reduced BM delivery. α-mCS1 EV delivery to the BM of MM-bearing mice was only slightly increased compared to native EVs, while off-target accumulation also increased. At the cellular level, no changes in EV delivery to MM cells were detected. In conclusion, while CS1 targeting enhances in vitro EV uptake by MM cells, in vivo biodistribution remains suboptimal. Further optimization is needed to improve EV-based drug delivery for MM.

Keywords:  anti‐CS1 nanobodies; biodistribution; extracellular vesicles; multiple myeloma; targeted delivery

DOI:  https://doi.org/10.1002/jev2.70325
J Nanobiotechnology. 2026 Jun 17.

Vitamin A-coupled MSCs- derived extracellular vesicles relieve acute liver injury by targeting hepatic stellate cells to deliver REDD1.

Tingjuan Huang, Zixu Li, Xinrui Shi, Xinyu Feng, Linyun Wei, Xiaonan Li, Junjie Ren.

  Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) offer great potential for treating liver injury. However, owing to their intrinsic surface characteristics, bare EVs are non-specifically distributed in the liver tissue after systemic administration, leading to limited therapeutic efficacy. Acute liver injury, often induced by acetaminophen overdose, can progress to life-threatening fibrosis, with hepatic stellate cells (HSCs) recognized as central drivers of this pathological process. While regulated in development and DNA damage response 1 (REDD1) has demonstrated antifibrotic effects by inhibiting HSCs activation, its clinical application has been hindered by challenges in targeted delivery. Utilizing the natural affinity of vitamin A (VA) for retinol binding protein receptors on HSCs, this study addresses the critical need for targeted therapies in acute liver injury by developing a novel delivery system based on VA-conjugated EVs (V-EVs) to transport the therapeutic gene REDD1 specifically to activated HSCs (aHSCs). After loading with REDD1 (V-EVREDD1), the system showed enhanced cellular uptake in activated HSCs in vitro and effective hepatic accumulation in vivo. Treatment with V-EVREDD1 significantly suppressed HSCs activation, reduced inflammation and hepatocyte apoptosis, improved liver function, and alleviated liver fibrosis in experimental models. This work highlights a promising strategy that combines targeted vesicle delivery with gene therapy, offering a potential avenue for improving the precision and efficacy of treatments for liver injury and fibrosis.

Keywords:  Extracellular vesicles; Hepatic stellate cells; Liver injury; REDD1; Targeted delivery

DOI:  https://doi.org/10.1186/s12951-026-04686-7
J Extracell Vesicles. 2026 Jun;15(6): e70318

Engineered Nestin+ TSPC-Derived Exosomes Promote Tendon Repair Via Metabolic Reprogramming.

Linxiang Cheng, Junyu Guo, Junshu Zhang, Qiangqiang Zheng, Zhixiong Zhang, Jingyao Chen, Jinhan Zhang, Xiao Chen, Zi Yin.

  Tendon repair remains a substantial clinical problem with limited treatment options. While Nestin+ tendon stem/progenitor cells (TSPCs) are known to regulate tendon healing, their clinical translation faces challenges. Here, we show that exosomes derived from engineered Nestin-overexpressing TSPCs (Nes-EVs) significantly ameliorate tendinopathy in multiple mouse models. We isolated Nes-EVs following lentiviral Nestin overexpression and demonstrated their capacity to reduce cellular senescence and promote tenogenic differentiation in vitro. In collagenase-induced (WT and Nes-CreERT2;iDTR) and naturally aged murine tendinopathy models, Nes-EVs robustly restored motor function, improved tissue architecture, reduced senescence markers and restored collagen homeostasis. Integrated transcriptomic and metabolomic profiling revealed a hallmark enrichment of the pantothenate and CoA biosynthesis pathway in both Nestin+ TSPCs and their exosomes. Mechanistically, Nes-EVs enhanced mitochondrial function in tenocytes, increasing ATP production and diminishing oxidative stress thereby revitalizing cellular metabolism in damaged tendons. Our findings unveil a fundamental mechanism where Nes-EVs coordinate tendon metabolism and homeostasis, offering a promising acellular therapeutic strategy for tendinopathy.

Keywords:  engineered TSPC; exosomes; nestin; tendinopathy

DOI:  https://doi.org/10.1002/jev2.70318
Clin Exp Med. 2026 Jun 18.

Engineered small extracellular vesicles in hematologic malignancies: mechanisms, therapeutic strategies, and translational challenges.

Chou-Yi Hsu, Saidmurodkhon Murtazaev, Sally Hassan Zubair, Mohammad Abohassan, Pareshkumar N Patel, Gunjan Singh, Vimal Arora, Priya Priyadarshini Nayak, Muhammad Shahid Iqbal, Zahraa Khudhair Abbas.

  Hematologic malignancies remain among the most challenging cancers to treat due to genetic heterogeneity, clonal evolution, and therapy resistance. Extracellular vesicles (EVs), particularly small EV (sEV)-enriched populations, have emerged as active mediators of disease biology, contributing to tumor progression, immune evasion, and chemoresistance through intercellular transfer of bioactive cargo. Recent advances in EV engineering have repositioned these vesicles as programmable delivery platforms capable of transporting nucleic acids, proteins, and chemotherapeutic agents with improved targeting potential. Preclinical studies across multiple hematologic models demonstrate that engineered EVs can induce immune activation, modulate oncogenic signaling pathways, and partially overcome drug resistance. However, these findings remain largely confined to experimental settings, with limited standardization of loading efficiency, biodistribution, and functional potency. Clinically, EV-based applications in hematology are still at an early stage, with most studies focused on biomarker discovery and supportive therapies rather than direct antitumor interventions. In parallel, theranostic EV platforms and liquid biopsy approaches offer promising opportunities for minimally invasive disease monitoring, although their clinical validation remains incomplete. Artificial intelligence (AI) further enhances this field by enabling advanced biomarker analysis and guiding cargo design and targeting strategies, yet its therapeutic applications are still largely exploratory. Despite key challenges, including vesicle heterogeneity, donor variability, suboptimal cargo loading, and manufacturing constraints, these limitations are primarily technical and may be addressed through standardization and engineering optimization. Collectively, EV-based systems represent a promising but still maturing platform with the potential to contribute to next-generation precision oncology in hematologic malignancies.

Keywords:  Artificial intelligence; Engineered EVs; Extracellular Vesicles (EVs); Hematologic malignancies; Small Extracellular Vesicles (sEVs); Theranostics

DOI:  https://doi.org/10.1007/s10238-026-02216-1
Sci Rep. 2026 Jun 19.

A combinatorial therapeutic platform based on graphene-collagen cryogel and apoptotic vesicles for modulating hypertrophic scars.

Mengyuan Jiang, Xiyuan Mao, Lu Zhang.

  Graphene-based collagen hydrogels have demonstrated anti-fibrotic potential in various diseases; however, their therapeutic efficacy in hypertrophic scars (HS) remains largely unexplored. Adipose stem cells (ASCs) and their extracellular vesicles have been shown to regulate HS progression, yet the role of ASCs derived apoptotic vesicles (ASCs-ApoVs) has not been fully investigated. In this study, we developed graphene-incorporated type I collagen cryogel (G-GEL(C)) and collected ASCs-ApoVs. We evaluated their individual and combined capacity to regulate HS and explored the potential of G-GEL(C) as a delivery system for ASCs-ApoVs. G-GEL(C) significantly inhibited fibrosis in HS derived fibroblasts (HS-fibroblasts), as evidenced by the downregulation of COL1A1 (p < 0.001 for both protein and mRNA), α-SMA (p < 0.001 for protein; p < 0.0001 for mRNA), and Vimentin (p < 0.05 for protein; p < 0.0001 for mRNA). Additionally, G-GEL(C) suppressed cell proliferation (p < 0.0001) and lateral migration (p < 0.001). Treatment with ASCs-ApoVs also reduced COL1A1 (p < 0.01 for protein; p < 0.0001 for mRNA) and α-SMA (p < 0.05 for both protein and mRNA), while Vimentin transcription was also downregulated (p < 0.001). G-GEL(C), characterized by high porosity and selective adsorption capacity for ASCs-ApoVs, enabled efficient loading and delivery of these vesicles. In vivo, G-GEL(C) loaded with ASCs-ApoVs decreased the scar elevation index (SEI) (p < 0.05), reduced α-SMA expression (p < 0.0001), locally increased 8-OHdG levels and raised the proportion of M2 macrophages, indicating effective regulation of HS. ASCs-ApoVs exhibit anti-fibrotic effects in HS. G-GEL(C) functions both as a direct modulator of HS-fibroblast phenotypes and as an efficient carrier for apoptotic vesicles. Collectively, they form a potent combinatorial system that significantly attenuates hypertrophic scar.

Keywords:  Anti-fibrosis; Apoptotic vesicles; Cryogel; Graphene; Hypertrophic scar

DOI:  https://doi.org/10.1038/s41598-026-57477-3
Med Int (Lond). 2026 Jul-Aug;6(4):6(4): 42

Regenerative and molecular therapies for myocardial repair (Review).

Divina Mariya Puthooran, Adlin Tom, Anna Anna, Harini Sundaram, Yousra Anwar, Kirtick Poovendran.

  Despite considerable progress being made in reperfusion, drugs and device-based therapies, myocardial infarction remains a primary cause of heart failure due to irreversible cardiomyocyte loss and maladaptive ventricular remodeling. Conventional surgical and interventional methods cannot regenerate functional myocardium, although they can restore perfusion. Limited endogenous cardiac renewal has driven the development of regenerative, molecular and bioengineering-based therapies aimed at myocardial repair after MI. The present narrative overview summarizes current approaches, including gene and RNA therapeutics, cell-based therapies, extracellular vesicles, engineered cardiac patches and pharmacological strategies. Only modest improvements in left ventricular function were shown in early clinical trials employing mesenchymal stromal cells and bone marrow-derived mononuclear cells; these benefits were mostly attributable to immunomodulatory and paracrine effects rather than true remuscularization. Recent advancements, including cardiac progenitor cells, allogeneic platforms and intraoperative delivery during coronary artery bypass grafting, improved safety but showed mixed outcomes. Induced pluripotent stem cell-derived cardiomyocytes and engineered cardiac patches are a step toward structural myocardial replacement with encouraging preclinical and early human safety data; however, problems with arrhythmogenic risk, immunological rejection, scalability and long-term durability remain unresolved. Parallel developments in gene and RNA therapies, particularly cardiotropic adeno-associated viral vectors, lipid nanoparticle-mediated mRNA delivery and RNA interference, have highlighted the importance of vector design, myocardial targeting and appropriate molecular selection, as evidenced by the inconsistent clinical outcomes of SERCA2a-based gene therapy. Pharmacological management of post-myocardial infarction inflammation, fibrosis, metabolism, and cellular senescence promotes regenerative methods by improving the cardiac milieu and decreasing detrimental remodeling. Both regenerative and molecular therapies have shown encouraging effects on cardiac repair, but successful clinical translation remains a work in progress. With ongoing technological advances and carefully controlled clinical studies, these innovative approaches could ultimately provide effective treatments to regenerate the damaged myocardium and improve outcomes for patients.

Keywords:  anti-inflammatory therapy; canakinumab; cardiovascular outcomes; colchicine; myocardial remodeling; myocardial repair; post-myocardial infarction inflammation; regenerative therapies

DOI:  https://doi.org/10.3892/mi.2026.326
Mol Cancer. 2026 Jun 20.

Extracellular vesicles in solid tumors: from tumor ecology to engineered therapeutics.

Wenxun Cai, Yuhang Chen, Suoyi Dai, Chien-Shan Cheng, Lianyu Chen.

  Extracellular vesicles (EVs) are important mediators of intercellular communication in solid tumors. Released by malignant, stromal, immune, and microbial cells, they influence tumor evolution by transferring proteins, nucleic acids, lipids, and metabolites that reshape local and systemic signaling. Current evidence implicates EVs in tumor microenvironment remodeling, metastatic niche formation, immune regulation, and adaptive responses to metabolic and therapeutic stress. However, these functions are highly context-dependent and remain unevenly supported across tumor types, disease stages, and experimental systems. Mechanistically, EV production is increasingly understood not as a constitutive secretory event, but as an adaptive output of intracellular trafficking and metabolic programs that govern vesicle fate, cargo selection, and release under stress. The same properties that complicate biological interpretation-including heterogeneity, membrane plasticity, and context-dependent cargo sorting-also make EVs attractive candidates for therapeutic engineering. In this Review, we critically examine EV biology in solid tumors by connecting biogenesis, trafficking control, lipid metabolism, and functional heterogeneity with emerging engineering strategies, including source selection, surface modification, cargo loading, and hybrid engineering strategies. We further discuss the major barriers that continue to limit clinical translation, particularly biological heterogeneity, isolation-dependent variability, incomplete mechanistic resolution, manufacturing scalability, and regulatory standardization. By distinguishing more established principles from emerging or model-restricted findings, this Review aims to provide a balanced assessment of both the opportunities and the current limitations of EV-based diagnostics and therapeutics.

Keywords:  Cancer immunotherapy; Drug delivery; EV engineering; Extracellular vesicles; Liquid biopsy; Metastasis; Solid tumors; Therapy resistance; Translational challenges; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02705-7
Mater Today Bio. 2026 Jun;38 103271

Enhancing the regenerative potential of MSC-derived exosomes via 3D microenvironment modulation for cartilage repair.

Hao Wang, Jie Wu, Guangzhao Tian, Zhijie Zhao, Mingxue Chen, Quanyi Guo, Yayi Xia.

  Articular cartilage defects remain a major clinical challenge due to their poor self-repair capacity. Mesenchymal stem cell (MSC)-derived exosomes have emerged as promising cell-free therapeutics; however, conventional two-dimensional (2D) cultures yield exosomes with limited bioactivity. Here, we engineered hierarchical macro-microporous scaffolds using gelatin methacryloyl (GelMA) hydrogel and cartilage extracellular matrix (ECM) to establish biomimetic three-dimensional (3D) microenvironments for MSC culture. This approach yielded three distinct exosome types-2D-Exo, GelMA-derived exosomes (G-Exo), and ECM-derived exosomes (E-Exo). Compared with 2D-Exo, 3D-derived exosomes significantly enhanced MSC proliferation, migration, chondrogenic differentiation, immunomodulation, and chondrocyte protection under inflammatory conditions, with E-Exo exhibiting the most potent effects. In vivo, E-Exo combined with a decellularized cartilage ECM (DCM) scaffold promoted robust hyaline cartilage regeneration in a rat model. Mechanistically, we identify a key pathway by which E-Exo drives chondrogenesis: they are enriched in miR-503-5p, which suppresses Smad7 to enhance TGF-β/Smad2/3 signaling. These findings highlight ECM-based 3D culture as an effective strategy to optimize exosome bioactivity and provide a clinically translatable approach for cell-free cartilage regeneration.

Keywords:  Cartilage regeneration; Extracellular matrix scaffold; MSC-Derived exosomes; Three-dimensional culture

DOI:  https://doi.org/10.1016/j.mtbio.2026.103271
Biomater Sci. 2026 Jun 08.

Dual-targeting macrophage membrane nanosystem enhances radiotherapy-induced antitumor immunity via synergistic nuclear and mitochondrial DNA damage.

Guangyu Ju, Qi Ding, Hongcang Gu, Rao Liu, Xiao Liu, Zimeng Wang, Kaiwei Wang, Yuan Ping, Jian You, Shuanghu Yuan, Junchao Qian.

Radiotherapy (RT) can trigger immune-related signaling in addition to its direct cytotoxic effects. However, in many cases, this immune activation is not strong enough to produce durable antitumor immunity. One important reason is that RT-induced nuclear DNA damage mainly activates the DNA damage response (DDR), which in turn dampens inflammatory signaling and restricts further immune amplification. Previous studies have suggested that mitochondrial stress participates in innate immune regulation through the cytosolic accumulation of mitochondrial nucleic acids; nevertheless, effective approaches to enhance mitochondrial stress during RT, especially in brain tumors where delivery is limited, remain to be established. Here, we developed a macrophage membrane-encapsulated, KLA-modified gold nanoparticle system (MKA) to reinforce mitochondrial-associated stress under RT and improve tumor delivery efficiency. Guided by inflammation-associated homing and RT-induced local inflammatory priming, MKA exhibits enhanced accumulation in brain tumors with a compromised blood-brain barrier. After irradiation, MKA localizes to mitochondria, induces mitochondrial membrane depolarization and increased permeability, and promotes cytosolic accumulation of mitochondrial RNA together with activation of the RIG-I-MAVS pathway, leading to elevated type I interferon signaling. In line with these effects, combined MKA and RT treatment enhances intratumoral CD8+ T-cell infiltration and suppresses glioma growth. Collectively, these findings suggest that strengthening mitochondrial-associated stress, together with inflammation-guided delivery, can potentiate RT-induced innate immune signaling and improve radiotherapy-associated immune responses in brain tumors.

DOI: https://doi.org/10.1039/d6bm00279j
ACS Pharmacol Transl Sci. 2026 Jun 12. 9(6): 1365-1379

Exosomal microRNAs in Periodontitis: From Molecular Footprints to Clinical Frontiers.

Maaz Anwer Memon, Danial Qasim Butt, Noriko Mizusawa, Muhammad Shahrukh Khan Sadiq, Wan Nazatul Shima Shahidan.

  Periodontitis is a widespread chronic inflammatory disease driven by host-microbial interactions and immune dysregulation, often resulting in alveolar bone loss and systemic complications. Exosomes, small extracellular vesicles enriched with microRNAs (miRNAs), have emerged as central modulators of these processes, mediated intercellular communication, and influenced inflammation, immunity, tissue homeostasis, and host-pathogen interactions in the periodontal microenvironment. Existing literature has identified their diagnostic relevance; however, a comprehensive framework connecting molecular mechanisms to clinical applications remains lacking. This narrative review proposes an integrative conceptual framework that illustrates the progression from exosomal miRNA biogenesis to their regulatory roles in periodontal disease, linking microbial triggers, immune modulation, and their emerging clinical relevance. We trace the molecular footprints of these exosomal miRNAs, particularly miR-146a, miR-155, and miR-223, and assess their dynamic roles as both biomarkers and regulatory agents in inflammation and tissue remodeling. Recent analytical advances, including systems biology, multiomics integration, and network modeling, are examined for their potential to decode complex miRNA-mediated pathways. Integration of transcriptomic, proteomic, and exosomal data is highlighted as a promising approach to enhance mechanistic insights and predictive accuracy. We also evaluate emerging diagnostic and therapeutic applications of exosomal miRNAs, particularly their potential in noninvasive biomarker development and targeted regenerative strategies. Key translational challenges are addressed, including the lack of standardized isolation protocols, interindividual biological variability, and the need for in vivo validation. Future directions should prioritize the development of engineered exosomes for targeted miRNA and anti-inflammatory delivery, alongside exosomal miRNA-based biosensors for real-time, minimally invasive disease monitoring. By bridging molecular footprints with emerging analytical approaches, this review offers a forward-looking perspective on the translational potential of exosomal miRNAs in periodontology, demonstrating their potential in advancing precision diagnostics and targeted therapeutics.

Keywords:  clinical; exosomal miRNA; exosomes; miRNA; periodontitis

DOI:  https://doi.org/10.1021/acsptsci.6c00155
Biomaterials. 2026 Jun 04. pii: S0142-9612(26)00390-X. [Epub ahead of print]335 124366

In situ macrophage CAR programming via ROS-responsive microneedles enhances efferocytosis and promotes mucosal regeneration.

Yuxin Qian, Wentao Wang, Mingzhe Xin, Haonan Ding, Yi Shuai, Zelong Hu, Xuwen Wang, Shijia Huang, Rui Mu, Ming Zhang, Lei Jin.

  Radiotherapy for head and neck cancer frequently induces severe radiation-induced oral mucositis (RIOM), in which excessive reactive oxygen species (ROS), defective macrophage efferocytosis, and persistent inflammation form a self-amplifying pathological loop that delays mucosal repair. Current symptomatic treatments are insufficient to simultaneously suppress oxidative stress and restore immune-mediated clearance of damaged cells. Here, we developed a detachable microneedle patch with ROS-responsive tips (PTC MN) for localized in situ macrophage programming within RIOM lesions. The PTC MN was fabricated from a PPBA-TA-PVA hydrogel matrix, which combines intrinsic ROS-scavenging capacity with oxidative stress triggered degradation, and loaded with engineered hybrid nanovesicles (HLENs-CAR) carrying a plasmid encoding CAR-ectoCRT-IL-4. This design enabled local delivery of gene-loaded nanovesicles, macrophage-targeted genetic programming, and sustained retention of the therapeutic payload in the injured mucosa. In a murine RIOM model, PTC MN accelerated mucosal epithelial regeneration, reduced oxidative stress and inflammatory infiltration, enhanced reparative macrophage responses, and attenuated fibrosis-associated tissue remodeling. Functionally, the platform enhanced macrophage efferocytosis, promoted IL-4-associated reparative polarization, and shifted the lesion microenvironment toward inflammation resolution and tissue regeneration. Collectively, this study establishes a smart in situ immunomodulation strategy that integrates ROS-responsive microneedle delivery with CAR-macrophage programming, providing a potential therapeutic paradigm for refractory mucosal injury.

Keywords:  CAR-Macrophage; Efferocytosis; Microneedles; ROS-Responsive biomaterials; Radiation-induced oral mucositis (RIOM)

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124366
Colloids Surf B Biointerfaces. 2026 Jun 11. pii: S0927-7765(26)00491-1. [Epub ahead of print]267 115903

ROS-responsive bio-hybrid probiotics for synergistic acute lung injury therapy.

Yi Deng, Peng-Peng Jia, Ni Zuo, Gui-Ting Huang, Zi-Han Yang, Yong-Yu Li, Zhu-Qing Wang, Dong-Xue Li, Mao-Qiang Yang, Zhi-Xiang Dong, Yu Gao, Kai Qian.

  Acute lung injury (ALI) features uncontrolled inflammation and oxidative stress that drive rapid deterioration and high mortality. While probiotics offer a promising vehicle for localized therapeutic delivery, their application in ALI is hindered by limited immunomodulatory activity and insufficient retention within inflamed lung tissue. Here, we report a dual-functional engineered Lactobacillus paracasei that couples cytokine-based immune regulation with microenvironment-responsive antioxidation. Through synthetic biology, the strain was programmed to secrete interleukin-4 (IL-4). A subsequent material-assisted surface modification enhanced the bacterium's ROS scavenging capability and facilitated improved therapeutic effects in inflamed lung tissue. In vitro, the engineered strain markedly suppressed TNF-α and IL-6 production and reduced intracellular ROS. In LPS- and Pseudomonas aeruginosa - induced ALI mouse models, treatment significantly attenuated lung inflammation, alleviated histopathological injury, and decreased the lung wet/dry ratio, with therapeutic benefits accumulating over time. Metabolomic profiling further revealed that the intervention reshaped the pulmonary microenvironment, notably elevating host-beneficial metabolites such as indole-3-butyric acid. Collectively, this work establishes a synergistic probiotic strategy integrating synthetic biology and responsive materials engineering to achieve targeted delivery, immune modulation, and oxidative stress relief. The engineered probiotic demonstrates potent therapeutic efficacy in ALI and represents a versatile platform for managing inflammation-associated respiratory diseases.

Keywords:  Acute Lung Injury (ALI); Bio-hybrid Interface; Engineered Probiotics; Interleukin-4 (IL-4); ROS-responsive Materials

DOI:  https://doi.org/10.1016/j.colsurfb.2026.115903
Biomater Adv. 2026 Jun 10. pii: S2772-9508(26)00311-0. [Epub ahead of print]188 215013

A Polydopamine-coated Engineered Type II Collagen Scaffold for Motor Neuron Organization and Spinal Cord Injury Regeneration.

Liang Ma, Bangheng Liu, Zhen Zhang, Huiqun Zhou, Cijun Shuai, Yi Zhang, Dong-An Wang.

  Spinal cord injury (SCI) leads to severe motor neuron depletion and glial scar formation, limiting endogenous regeneration and motor functional recovery. While engineered collagen scaffolds offer a promising strategy for supporting neural repair, the optimal scaffold composition and functionalization remain to be explored. This study investigates the efficacy of a novel polydopamine-coated engineered type II collagen (Col 2-PDA) scaffold and evaluates its efficacy for inducing differentiation of motor neural progenitors (MNPs) into motor neurons and for promoting motor functional recovery in the SCI model. In vitro, the Col 2-PDA scaffolds significantly enhance MNPs proliferation and differentiation into motor neurons while reducing apoptosis compared to crosslinked type I collagen controls. In the transected SCI model, hindlimb motor function improved. The Col 2-PDA scaffolds attenuate astrogliosis, suppress glial scar formation, and potently modulate the local immune response, as evidenced by an increased proportion of CD206+ macrophages. Critically, the lesion site in the Col 2-PDA group exhibits robust expression of the axonal regeneration marker GAP43, along with the formation of SYP+ new synaptic connections. Collectively, these findings prove that the engineered Col 2-PDA scaffolds provide a conducive microenvironment for motor neuron organization and that PDA functionalization synergistically enhances the therapeutic potential by mitigating inflammation, driving anti-inflammatory macrophage polarization, and facilitating neurogenesis and axon regeneration. Thus, the Col 2-PDA scaffolds represent a multifunctional platform for advanced neural tissue engineering and SCI treatment.

Keywords:  Engineered type II collagen; Polydopamine; Regeneration; Spinal cord injury

DOI:  https://doi.org/10.1016/j.bioadv.2026.215013
J Adv Pharm Technol Res. 2026 Apr-Jun;17(2):17(2): 191-197

Evaluation of the combination of chitosan hydrogel crosslinker and dental pulp stem cell-derived exosomes on osteoblast viability and differentiation.

Endang Winiati Bachtiar, Irene Edith Rieuwpassa, Turmidzi Fath, Juni Handajani, Widya Lestari.

  Dental pulp stem cell (DPSC) has gained attention as a cell-free therapeutic approach to enhance bone regeneration. However, the degradation of exosomal biomaterials limits their application, which may be overcome by using an injectable chitosan hydrogel crosslinker (ICHC) as a natural polymeric carrier. ICHC was prepared and loaded with exosomes derived from DPSCs. Cytotoxicity, calcium deposition, nanoparticle tracking analysis (NTA), and transmission electron microscopy (TEM) were conducted to assess biocompatibility, mineralization capacity, and structural characteristics. The cell viability of ICHCs, exosome 5 ng/mL, and exosome-loaded ICHC 0.6% ranged from 95% to 132%. NTA analysis revealed particle sizes of 147.5 nm for exosomes and 377.5 nm for exosome-loaded ICHC, with concentrations of 4.6 × 106 and 1.4 × 107 particles/mL, respectively. TEM further validated effective encapsulation, revealing electron-dense particles dispersed throughout the ICHC hydrogel matrix. The combination of exosome-loaded ICHC achieved 100% viability in osteoblast cells and promoted more elongated cell morphology compared to the control, suggesting a safe and effective cell-free material for bone regeneration therapy.

Keywords:  Bone regeneration; cell survival; exosomes; injectable chitosan hydrogel crosslinker; osteoblasts

DOI:  https://doi.org/10.4103/JAPTR.JAPTR_312_25
J Nanobiotechnology. 2026 Jun 19.

Biomimetic fusion nanosystem from ginger exosomes and tumor cell membranes: boosting PLK1-targeted therapy in BRCA-heterogeneous HGSOC.

Xue Zhou, Yutang Huang, Chenyi Li, Wenlu Mo, Weifeng Xia, Ruiqin Du, Lanxiang Wu, Hongbo Zhao.

  High-grade serous ovarian carcinoma (HGSOC) remains a lethal malignancy with few effective therapeutic options. In this study, we systematically evaluated the anti-tumor effect of Bi2536, an inhibitor of Polo-like kinase 1 (PLK1), in HGSOC, and clarified its mechanism. Bi2536 inactivates PLK1, leading to the subsequent inactivation of cyclin-dependent kinase 1 (CDK1). This disruption triggers a cascade of antitumor effects, including G2/M phase arrest, induction of mitochondrial apoptosis, and suppression of cell migration and invasion. Furthermore, we identified circadian oscillations in PLK1 expression both in HGSOC cells and in vivo xenograft models. To enhance therapeutic precision and minimize systemic toxicity, we engineered a biomimetic nano-delivery system for Bi2536. This integrated platform combines chemotherapy and chemodynamic therapy (CDT), significantly improving antitumor outcomes. Importantly, synchronizing Bi2536 administration with the circadian peaks of PLK1 expression further augmented its therapeutic efficacy. In summary, our work establishes that the combination of Bi2536 with a biomimetic nano-delivery system, together with its chronotherapeutic administration, constitutes a highly promising and multifaceted strategy for the treatment of HGSOC.

Keywords:  Biomimetic nanoplatform; Chronotherapy; Circadian rhythm; High-grade serous ovarian cancer; PLK1 inhibitor

DOI:  https://doi.org/10.1186/s12951-026-04656-z
Front Immunol. 2026 ;17 1824799

Electroacupuncture alleviates myocardial ischemia-reperfusion injury by targeting and inhibiting NLRP3 inflammasome-mediated cardiomyocyte pyroptosis via serum exosomal miR-22-3p.

Jian Xiong, Ying Wei, Yunnan Liu, Fayang Ling, Yi Zhao, Yu Liu, Yuxin Sun, Dehua Li, Mingsheng Sun, Dingjun Cai, Wenchuan Qi, Qianhua Zheng, Fanrong Liang.

   Background: Myocardial ischemia-reperfusion injury (MIRI) presents a significant challenge to the effectiveness of reperfusion therapy in severe ischemic heart disease. One of the core pathological mechanisms of MIRI is NLRP3 inflammasome-mediated cardiomyocyte pyroptosis. While electroacupuncture (EA) has demonstrated efficacy in mitigating MIRI, its potential to target and inhibit NLRP3 inflammasome-mediated cardiomyocyte pyroptosis in the context of MIRI remains unclear. Additionally, the mechanism through which local EA may remotely influence the heart to alleviate MIRI is not well understood.
Objective: This study aims to explore the protective effects and molecular mechanisms of EA targeting NLRP3 inflammasome-mediated myocardial cell death in MIRI, focusing on the role of serum exosomes.
Methods and results: An animal model of MIRI was established by ligating the left anterior descending coronary artery, and EA was applied at the Neiguan (PC6) acupoint. Cardiac function, myocardial infarction area, serum myocardial enzymes, inflammatory factors, and myocardial cell pathological changes were assessed using echocardiography, Evans-TTC staining, ELISA, and H&E staining to confirm the therapeutic effect of EA in reducing MIRI. The NLRP3 agonist Nigericin was applied, and the expression levels of key genes and proteins related to NLRP3-mediated apoptosis were measured by Western blotting and RT-qPCR, confirming that EA alleviates MIRI by targeting and inhibiting NLRP3-mediated myocardial apoptosis. The role of serum exosomes in inhibiting NLRP3 inflammasome-mediated cardiomyocyte pyroptosis was then tested in a cardiomyocyte hypoxia/reoxygenation model. Exosomes from serum samples of AMI-PCI patients (with or without standard EA) and from MIRI model rats were isolated. Small RNA sequencing was performed to identify key effector miRNAs post-EA. Our findings revealed that miR-22-3p was significantly upregulated in serum exosomes following EA. Further validation demonstrated that miR-22-3p mitigates MIRI by targeting NLRP3 to inhibit cardiomyocyte pyroptosis, as confirmed through target gene prediction, in vitro cell experiments, and in vivo animal studies.
Conclusion: This study provides evidence that EA reduces MIRI by upregulating miR-22-3p in serum exosomes, which in turn targets and inhibits NLRP3 inflammasome-mediated cardiomyocyte pyroptosis, thereby reducing severe myocardial injury.

Keywords:  NLRP3; electroacupuncture; exosomes; miR-22-3p; myocardial ischemia reperfusion injury; pyroptosis

DOI:  https://doi.org/10.3389/fimmu.2026.1824799
Oncol Rev. 2026 ;20 1814540

Signaling pathway mechanisms in pancreatic ductal adenocarcinoma tumor microenvironment and emerging targeting strategies for improved prognosis.

Tosin Akinsipe, Caroline O Odewumi, Lekan Latinwo, Omorose O Aghimien, Musiliyu A Musa, Philip O Igbinoba, Anthony L Simons, Monica O Aghimien.

  Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by a dense desmoplastic stroma and a profoundly immunosuppressive tumor microenvironment (TME). The TME plays a major role in tumor progression, metastasis, and resistance to conventional therapies through a network of dysregulated signaling pathways, including KRAS, PI3K/AKT/mTOR, Raf/MAPK/ERK, TGF-β, NF-κB, Notch and Hedgehog. Moreover, cellular components such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and regulatory T cells (Tregs) drive immune evasion and therapeutic resistance via cytokine signaling axes, including IL-6/STAT3 and CXCL12/CXCR4. Recent advances in nanomedicine have introduced polymeric nanoparticles as promising delivery vehicles for targeted disruption of these aberrant pathways. Polymeric nanoparticles are engineered to enhance bioavailability, tissue penetration, and selective delivery, co-deliver small-molecule inhibitors, siRNA, or immunomodulatory agents directly to the TME. This approach offers a strategy to overcome biological barriers, reprogram the stroma, and sensitize tumors to immunotherapy and chemotherapy. This review comprehensively examines the signaling mechanisms of PDAC in the TME, discusses current therapeutic strategies targeting these pathways, highlights challenges, including resistance and adverse effects, and explores future directions to optimize pancreatic cancer treatment by modulating this key signaling axis with nanomedicine.

Keywords:  PDAC; improved prognosis; pancreatic cancer; polymeric nanoparticles; signaling pathway; targeted delivery; tumor microenvironment

DOI:  https://doi.org/10.3389/or.2026.1814540
N Biotechnol. 2026 Jun 19. pii: S1871-6784(26)00080-4. [Epub ahead of print]

Metabolic engineering of Saccharomyces cerevisiae sphingolipid pathways for enhanced phytoceramide production.

Jordi Guixeras-Carreras, Marc Caballé, Pablo Leivar, Marjan De Mey, Antoni Planas, Cristina Fornaguera, Margalida Artigues, Magda Faijes.

  Phytoceramides are essential sphingolipids that support skin barrier integrity and hydration, making them valuable for cosmetic and pharmaceutical applications. However, their intricate structures and low natural abundance pose significant challenges for scalable production. Here, we present an integrated metabolic engineering and lipidomics study aimed at enhancing phytoceramide production in Saccharomyces cerevisiae. We implemented three strategies: (i) overexpression of SUR2 (sphinganine C4-hydroxylase) to boost phytosphingolipid formation; (ii) deletion of SCS7 (ceramide α-hydroxylase) to redirect flux toward non-hydroxylated phytoceramides; and (iii) overexpression of ISC1 (inositol phosphosphingolipid phospholipase) to recycle complex sphingolipids into ceramide pools. SUR2 overexpression showed the highest transcript levels, whereas lipidomics revealed that scs7Δ produced the highest phytoceramide enrichment with a 15-fold increase in phytoceramide abundance relative to the wild type. In terms of relative abundance within the quantified ceramide pool, phytoceramides increased from 5% in wild type to 46% in the SUR2-OE strain and 75% in the scs7Δ strain. The combined scs7Δ SUR2-OE strain did not exhibit additive metabolic effects on the lipid profile. The presence of residual hydroxylated ceramides indicated intrinsic regulatory constraints, aligning with the bypass mechanism proposed here whereby ceramide synthases can use pre-hydroxylated acyl-CoA. Importantly, this work contributes a comprehensive lipidomic profiling of S. cerevisiae, enabling clear discrimination between engineered and wild type strains and identification of genotypes exerting the greatest impact on phytoceramide accumulation. This approach advances sphingolipid pathway modulation and positions S. cerevisiae as a valuable model for studying phytoceramide-focused remodeling.

Keywords:  Saccharomyces cerevisiae; ceramide; lipidomics; metabolic engineering; phytoceramide; sphingolipids

DOI:  https://doi.org/10.1016/j.nbt.2026.06.005
Nat Commun. 2026 Jun 17.

IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma.

Eleni Panagioti, Hunter J Kelley, Alexander L Ling, Leinal Sejour, Shikha Saini, William F Goins, Daniel Roberts, Sotiris Sotiriou, J Bryan Iorgulescu, Karen O Dixon, Michael B Yaffe, Ioannis S Vlachos, Maria G Castro, Sean E Lawler, Gordon J Freeman, Vijay K Kuchroo, E Antonio Chiocca, Charles H Cook.

Oncolytic virotherapy represents a promising yet under-explored approach for precision cancer treatment, particularly when tailored to tumor-specific molecular profiles. Patients with high-grade isocitrate dehydrogenase (IDH) mutant astrocytomas have limited treatment options and poor prognoses. Here, we investigate the therapeutic efficacy of rQNestin34.5 v.2 (CAN-3110), an engineered oncolytic herpes simplex virus 1 (oHSV-1), in IDH1-R132H-mutant diffuse gliomas. We demonstrate that the IDH1-R132H mutation enhances glioma susceptibility to viral infection through upregulation of Nectin-1, the main HSV-1 entry receptor. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, creating a permissive microenvironment that facilitates viral replication and tumor cell apoptosis. In immunocompetent murine glioma models, intratumoral administration of rQNestin34.5 v.2 induces robust antitumor immune activation, including increased immune infiltration and systemic IFN-γ release. However, elevated expression of poliovirus receptor (PVR) and the immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating leukocytes suggests a potential resistance mechanism to virotherapy. Combining rQNestin34.5 v.2 with TIGIT blockade enhances therapeutic efficacy compared to monotherapy, identifying IDH1-R132H as a potential predictive biomarker for oncolytic virotherapy response.

DOI: https://doi.org/10.1038/s41467-026-73974-5
Immunol Res. 2026 Jun 15. pii: 58. [Epub ahead of print]74(1):

IL-6R-CD3-engineered regulatory T cells alleviate neuropathic pain by remodeling the neuroimmune microenvironment.

Chunhua Lu, Peng He, Shan Wu, Xinxin Liao, Tingting Xu, Wei Wang.

  Chronic neurological condition Neuropathic pain is marked by sustained neuronal sensitization. Regulatory T cells are crucial for preserving immune homeostasis. however, their stability and suppressive activity are often compromised within inflammatory environments generated after nerve injury, limiting their ability to restrain neuroinflammation. This study sought to determine whether genetically modified regulatory T cells expressing an interleukin-6 receptor-CD3ζ fusion receptor could enhance Treg persistence, functional capacity, and therapeutic benefit in a rat chronic constriction injury (CCI) model. CD4⁺CD25⁺ regulatory T cells were isolated from rat spleens and then transduced with a lentiviral vector expressing IL-6R-CD3ζ-IRES-GFP. The modified cells were subsequently evaluated in vitro for their proliferative capacity, susceptibility to apoptosis, and migratory behavior under inflammatory cytokine stimulation. To establish neuropathic pain, a chronic constriction injury model was generated by placing four loose chromic gut ligatures around the sciatic nerve at approximately 1-mm intervals proximal to the trifurcation. The animals then underwent adoptive transfer of either conventional regulatory T cells or IL-6R-CD3ζ-engineered regulatory T cells. Mechanical hypersensitivity was measured by behavioral testing, whereas flow cytometry together with molecular assays was applied to assess immune cell infiltration, the expression of inflammatory mediators, and the activation of intracellular signaling pathways in spinal cord tissue. Native Tregs did not effectively suppress CCI-associated neuroinflammation. Depletion of these cells exacerbated mechanical hypersensitivity, while adoptive transfer of unmodified Tregs conferred only limited analgesic effects. By contrast, IL-6R-CD3ζ-engineered Tregs retained cytokine-responsive migratory ability, displayed greater proliferative activity, and persisted longer in vivo. Transfer of the engineered Tregs significantly increased paw withdrawal thresholds and alleviated neuropathic pain. Mechanistically, this treatment reduced macrophage infiltration and shifted macrophages toward a less proinflammatory phenotype. It also markedly inhibited microglial activation and inflammatory mediator production, together with suppression of nuclear factor kappa B and mitogen-activated protein kinase signaling. In addition, neutrophil recruitment and effector functions were significantly reduced, including diminished secretion of IL-1β, TNF, IL-6, and matrix metalloproteinases as well as decreased oxidative stress. IL-6R-CD3 engineered Tregs remodel the neuroimmune after nerve injury by regulating macrophage, microglial, and neutrophil responses.

Keywords:  IL-6 receptor signaling; Microglia; Neuroinflammation; Neuropathic pain; Neutrophil infiltration; Regulatory T cells (Tregs)

DOI:  https://doi.org/10.1007/s12026-026-09791-1
Curr Protein Pept Sci. 2026 Jun 10.

Nanotherapeutic Interventions in Diabetic Wound Healing: Biomarker- Guided Mechanisms and Translational Prospects.

Pranjal Sachan, Jyotsana Dwivedi, Pranay Wal, Kamallochan Barman, Hanish Singh Jayasingh Chellammal, Selora Agasti, Ramenani Hari Babu, Abhijit Dutta.

   INTRODUCTION: Diabetes mellitus is a chronic metabolic disorder that is frequently complicated by impaired wound healing, resulting in diabetic foot ulcers, amputations, and long-term disability. Conventional wound management strategies often fail due to persistent inflammation, oxidative stress, vascular dysfunction, and neuropathy. Recent advances in nanotechnology and biomarker research have emerged as promising approaches to improve diabetic wound healing outcomes.
METHODS: A comprehensive literature review was conducted using PubMed, ScienceDirect, Elsevier, Web of Science, and Google Scholar to identify relevant studies published up to January 2025. Peerreviewed original research articles and reviews were screened using keywords related to diabetic wound healing, nanotherapeutics, nanoparticles, biomarkers, tissue engineering, and clinical translation.
RESULTS: Nanotherapeutic systems, including metallic nanoparticles, polymeric nanoparticles, nanofibres, lipid-based carriers, hydrogels, and bioengineered exosomes, have demonstrated antimicrobial, pro-angiogenic, anti-inflammatory, and antioxidant effects in preclinical and clinical studies. These systems promote accelerated wound closure, enhance collagen deposition, improve angiogenesis, and reduce the inflammatory burden. Additionally, emerging biomarkers, such as microRNAs, cytokines, and angiogenic factors, provide valuable insights into wound progression, therapeutic response, and tissue regeneration. The integration of biomarker monitoring with nanocarrier-based delivery systems supports a personalised and adaptive wound care strategy.
DISCUSSION: The combined application of nanotherapeutics and biomarker-based diagnostics addresses key pathological barriers in diabetic wound healing and offers improved therapeutic precision. However, translational challenges remain, including biosafety concerns, long-term toxicity, regulatory complexities, and variability in clinical outcomes.
CONCLUSION: Nanotechnology-based therapeutics integrated with biomarker-driven assessment represent a promising and evolving paradigm for DM wound management, with the potential to enhance healing efficiency and support personalised treatment approaches; further large-scale clinical validation is warranted.

Keywords:  Diabetic wound healing; angiogenesis; biomarkers; drug delivery systems.; growth factors; nanomedicine; nanoparticles; tissue regeneration

DOI:  https://doi.org/10.2174/0113892037446299260428105758
Acta Biomater. 2026 Jun 17. pii: S1742-7061(26)00394-6. [Epub ahead of print]

Hyaluronic acid-coated metal-organic framework for co-delivery of Sirtuin 3 gene and zinc to inhibit liver fibrosis.

Jisun Jung, Minyoung Jin, Naeun Park, Hani Choi, Kun Na.

  Liver fibrosis is characterized by excessive accumulation of extracellular matrix and disruption of hepatic sinusoidal architecture. However, effective therapies targeting microvascular dysfunction and immune imbalance remain limited. In this study, we present hyaluronic acid (HA)-coated zeolitic imidazolate framework-8 (ZIF-8) formulations (HDZs) loaded with sirtuin 3 (SIRT3) plasmid DNA, designed for the co-delivery of SIRT3 and bioavailable zinc ions to restore hepatic homeostasis. The HA coating promoted cellular uptake across multiple hepatic cell types, including hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and macrophages. In vitro, the nanoplatform suppressed stellate cell activation, maintained LSEC fenestrae, and induced macrophage polarization toward an anti-inflammatory phenotype. The pH-responsive disassembly of ZIF-8 enabled efficient intracellular release of SIRT3, while the simultaneous release of zinc ions contributed to cytoprotective effects. In fibrotic mouse models, the treatment significantly reduced collagen deposition, preserved sinusoidal structure, and promoted M2-dominant macrophage polarization, accompanied by improved liver function and elevated hepatic zinc levels. These results demonstrate a combined anti-fibrotic effect achieved through coordinated genetic modulation and micronutrient support. Collectively, this HDZ platform represents a multifunctional non-viral gene delivery strategy for liver fibrosis and offers potential for treating other chronic liver diseases involving mitochondrial dysfunction, immune dysregulation, and microvascular injury. STATEMENT OF SIGNIFICANCE: Liver fibrosis lacks effective treatments that simultaneously address structural damage, immune imbalance, and mitochondrial dysfunction. This study introduces a hyaluronic acid-coated ZIF-8 nanoplatform that co-delivers a mitochondrial regulatory gene and bioavailable zinc, enabling coordinated genetic and micronutrient modulation within the fibrotic liver. Unlike conventional approaches that target a single pathway or cell type, this platform engages hepatic stellate cells, liver sinusoidal endothelial cells, and macrophages, leading to reduced fibrosis, preserved sinusoidal architecture, and immune reprogramming in vivo. By integrating non-viral gene delivery with controlled zinc release, this work provides a multifunctional strategy for restoring hepatic homeostasis and expands the therapeutic potential of metal-organic framework-based nanomedicine for chronic liver diseases.

Keywords:  Gene delivery; Liver fibrosis; SIRT3; ZIF-8; Zinc ion

DOI:  https://doi.org/10.1016/j.actbio.2026.06.032
Anticancer Agents Med Chem. 2026 Jun 18.

Extracellular Vesicles and Their Multifaceted Roles in Cancer: Current Evidence from a Narrative Review.

Himanshu Singh, Ranjeet Kumar Yadav, Anmol Dogra.

   INTRODUCTION: Extracellular Vesicles (EVs), including exosomes and microvesicles, are nanoscale, lipid bilayer-enclosed particles released by diverse cell types. They play a key role in intercellular communication by transferring proteins, lipids, and nucleic acids. In cancer, EVs contribute to remodelling the tumor microenvironment, enhancing angiogenesis, modulating immune responses, promoting metastasis, and driving therapeutic resistance.
AIM: This narrative review aims to highlight the biological importance and clinical relevance of EVs in cancer, focusing on their potential as biomarkers and therapeutic tools.
METHODS: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science. Studies on EV composition, isolation, and characterization methods, as well as recent advances in EV bioengineering, were critically examined to summarize their significance in oncology.
RESULTS AND DISCUSSION: Findings reveal that the molecular cargo of EVs reflects the physiological and pathological states of their source cells, supporting their role as non-invasive biomarkers for cancer detection and monitoring. EVs also regulate signaling pathways that sustain tumor heterogeneity and adaptability. Moreover, engineered EVs demonstrate strong potential as delivery systems for chemotherapeutic agents, RNA-based drugs, and immunomodulators, underscoring their translational value in targeted therapy.
CONCLUSION: EVs represent versatile tools in precision oncology. Although standardization and clinical validation remain challenges, ongoing research and technological progress may establish EV-based strategies as integral components of personalized cancer treatment.

Keywords:  EV Cargo; Extracellular vesicles; cancer.; exosomes; microvesicles; niche formation

DOI:  https://doi.org/10.2174/0118715206434074260407093116
Front Cell Dev Biol. 2026 ;14 1812373

Lipid nanoparticles and extracellular vesicles: emerging cell free therapeutic platforms for hepatobiliary cancers.

Gabriele Saccu, Sharmila Fagoonee.

  Hepatobiliary cancers are major contributors to cancer-related mortality, mainly due to late-stage diagnosis, poor prognosis, and limited effectiveness of current treatments in advanced disease. Standard therapies comprise surgical resection, liver transplantation, and systemic agents including tyrosine kinase inhibitors and immune checkpoint inhibitors, but their efficacy is often hindered by the development of drug resistance, underlying the urgent need for novel therapeutic strategies. Lipid nanoparticles (LNPs) have emerged as promising delivery vehicles due to their favorable physicochemical properties, enabling the transport of natural biomolecules or engineered drugs for targeted tumor therapy. LNPs are also being explored as platforms for cancer therapy and vaccines. Moreover, recent advances underscore the key role of extracellular vesicles (EVs) in modulating the tumor microenvironment, promoting tumor progression, chemoresistance, and escape from immune recognition and destruction (immune evasion) in hepatobiliary cancers. EVs are being investigated both as biomarkers for early detection and as therapeutic agents, with engineered or drug-loaded EVs showing potential for targeted drug delivery and tissue repair in liver diseases, including cancer. This review highlights the potential of cell-free therapeutic LNP- and EV-based platforms, standalone or in combination, for RNA, small molecules and proteins delivery in improving diagnosis and treatment outcomes in hepatobiliary cancers, in particular, hepatocellular carcinoma and cholangiocarcinoma.

Keywords:  biomarkers; cancer therapy; drug delivery; extracellular vesicles; hepatobiliary cancers; lipid nanoparticles; mRNA vaccine

DOI:  https://doi.org/10.3389/fcell.2026.1812373
Vaccine. 2026 Jun 16. pii: S0264-410X(26)00658-4. [Epub ahead of print]88 128849

Engineered OMVs of Salmonella displaying PlpE antigen provide effective protection against Pasteurella multocida infection in mice.

Zhili Luo, Liping Gu, Zheng Du, Zhen Cao, Bingan Zhu, Zhihui Zhang, Shengliang Cao, Yubao Li, Guodong Zhou.

  Pasteurella multocida is a major zoonotic pathogen that contributes to progressive atrophic rhinitis and the porcine respiratory disease complex in pigs, leading to significant economic losses in the swine industry. Current vaccines show limited efficacy and safety concerns. Here, we developed an OMV-based antigen display system using the signal peptide of OmpD derived from Salmonella Typhimurium to present the protective antigen PlpE. The engineered OMVs enabled surface localization of PlpE and were evaluated via intranasal immunization in mice. Immunization induced strong antigen-specific IgA and IgG responses, along with a Th1/Th17-biased cellular response. The resulting serum exhibited complement-dependent bactericidal activity against P. multocida. Upon challenge with a 10× LD50 dose, vaccinated mice showed significantly improved survival (80%) and reduced tissue damage. These findings demonstrate that engineered OMVs represent an effective antigen delivery platform for the control of porcine pasteurellosis.

Keywords:  Antigen display; Outer membrane vesicles (OMVs); Pasteurella multocida; PlpE; Signal peptide

DOI:  https://doi.org/10.1016/j.vaccine.2026.128849
Front Pharmacol. 2026 ;17 1849977

Molecularly engineered BODIPY photosensitizers for combined cancer phototherapy and immunotherapy.

Huixia Wang, Yangming Zhang, Mengjiao Zhou.

  BODIPY-based photosensitizers have attracted great interest in cancer phototherapy and immunotherapy due to their tunable structures, excellent photostability, and high molar extinction coefficients. However, conventional BODIPY dyes have inherent limitations, such as poor water solubility, shallow tissue penetration, oxygen dependence, and insufficient single-modality efficacy. To address these, recent studies have used molecular engineering (ring fusion, electronic modulation, supramolecular assembly, metal coordination) to enhance reactive oxygen species generation and photothermal conversion. Smart delivery systems with microenvironment responsiveness further enable tumor targeting and microenvironment remodeling. Importantly, BODIPY-mediated phototherapy combined with immunotherapeutic strategies (immune checkpoint blockade, pyroptosis/cuproptosis induction, cGAS-STING activation, etc.) achieves synergistic antitumor effects, transforming localized tumor ablation into systemic immunity. This review summarizes recent progress in molecularly engineered BODIPY photosensitizers, from molecular optimization and smart delivery to immune synergy, and discusses current challenges and future directions to promote their clinical translation.

Keywords:  BODIPY photosensitizers; immunotherapy; photodynamic therapy; photothermal therapy; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2026.1849977
J Control Release. 2026 Jun 15. pii: S0168-3659(26)00507-9. [Epub ahead of print]396 115104

Astrocyte-derived exosome-mediated siRNA delivery combined with quercetin-Mn complex promotes neural repair in spinal cord injury.

Jinlong Zhang, Guanhua Xu, Jiajia Chen, Hongxiang Hong, Pengfei Xue, Chunyan Ji, Zhanyang Qian, Mingjie Xia, Jiawen Xu, Chaochen Li, Tianyi Wang, Yuyu Sun, Zhiming Cui.

  Neuroinflammation and oxidative stress are pivotal drivers of neurological dysfunction following spinal cord injury (SCI). Consequently, precise modulation of pathological glial cells and amelioration of the neuronal microenvironment represent a promising therapeutic strategy. Herein, we developed an injectable, self-healing hydrogel system composed of oxidized sodium alginate, carboxymethyl chitosan, and tannic acid (OCT) for the sustained co-delivery of a Quercetin-Manganese complex (QM) and astrocyte-derived extracellular vesicles encapsulating siRNA (AEVs@siRNA). RNA sequencing revealed significant enrichment of the TNF and chemokine signaling pathways in SCI mice, with a notable upregulation of Serpina3n. This gene, predominantly expressed in astrocytes, modulates their reactive polarization. Leveraging the innate tropism of astrocyte-derived extracellular vesicles, we achieved targeted delivery of Serpina3n-targeting siRNA to astrocytes at the lesion site. This approach effectively suppressed the expression of Serpina3n, inhibiting the transition to a neurotoxic A1 phenotype and alleviating neuronal damage. Concurrently, the sustained release of QM NPs potently scavenged reactive oxygen species, significantly mitigating neuronal ferroptosis. Further mechanistic investigations demonstrated that this combinatorial system attenuated neuroinflammation by inhibiting NF-κB p65 signaling to reduce A1 astrocyte activation, and protected neurons by regulating the SLC7A11/GPX4 axis to counteract apoptosis and ferroptosis, both in vitro and in vivo. Consequently, this targeted delivery system represents a promising approach for enhancing therapeutic efficacy and promoting neural repair following SCI.

Keywords:  Hydrogel; Neuronal apoptosis; Spinal cord injury; Type A1 neurotoxic astrocytes; siRNA

DOI:  https://doi.org/10.1016/j.jconrel.2026.115104
World J Pediatr. 2026 Jun 13.

Transplantation of encapsulated fecal microbiota: research progress and future trends.

Mei-Le Lin, Hai-Nv Gao.

   BACKGROUND: Fecal microbiota transplantation (FMT) demonstrates significant efficacy in treating intestinal disorders, such as recurrent Clostridioides difficile infection (rCDI). However, traditional FMT relies on invasive delivery methods (e.g., colonoscopy or use of a nasoenteric tube) and lacks standardized donor screening, limiting its widespread clinical adoption and scalability. As a key formulation of live biotherapeutic products (LBPs), encapsulated FMT represents a transition from empirical microbial transfer to engineered biotherapeutics, offering a safer and more convenient approach for clinical application.
DATA SOURCES: This review synthesizes, compares, and integrates data in a narrative fashion from PubMed and the China National Knowledge Infrastructure.
RESULTS: Research on encapsulated FMT in adults has progressed toward standardization and the exploration of new indications. In contrast, pediatric studies remain primarily focused on rCDI treatment and lack large-scale randomized controlled trials. Evolution toward encapsulated, standardized products is driving a shift from whole-community microbial formulations toward more defined consortia and, ultimately, synthetic biology-based innovations. Concurrent significant regulatory challenges persist, as definitions of LBPs remain inconsistent and clear, harmonized international guidelines are yet to be established.
CONCLUSIONS: This review summarizes progress and emerging research priorities in encapsulated FMT while also examining current regulatory challenges and innovative directions within the LBP framework. Future developments are poised to advance encapsulated FMT from whole-community transplantation toward the precise modulation of functional microbial consortia. This progression will help drive microbial therapeutics toward greater standardization and personalization, offering improved treatment strategies for intestinal and other microbiome-associated diseases.

Keywords:  Encapsulated fecal microbiota transplantation; Live biotherapeutic products; Microbiome engineering; Pediatric applications; SER-109

DOI:  https://doi.org/10.1007/s12519-026-01056-z
Bioact Mater. 2026 Nov;65 246-267

The miR-212-3p/transferrin axis promotes bone regeneration by modulating iron homeostasis through Schwann cell Exosome-BMSCs communication.

Yukun Jia, Ningdao Li, Dagang Tang, Wendan Pu, Zhiqiang Feng, Yingtao Duan, Yafei Zhu, Juan Wang, Xiaoji Luo, Jun Zhang.

  Functional bone regeneration relies on cross talk between nerves and bone, yet the regulatory mechanisms linking Schwann cells (SCs) to osteoporotic bone marrow mesenchymal stem cells (OP-BMSCs) remain unclear. This study demonstrated that SC-Exosomes (Exos) promoted the osteogenic differentiation of OP-BMSCs, and miRNA-mRNA sequencing revealed that SC-Exos, which contained the key mediator miR-212-3p, facilitated osteogenesis by suppressing the ferroptosis pathway in OP-BMSCs. miR-212-3p overexpression combined with transferrin (TF) knockdown or overexpression confirmed that miR-212-3p suppresses TF expression and validated the role of the miR-212-3p/TF axis, which maintained iron homeostasis in BMSCs, alleviated iron overload and oxidative stress, and promoted osteogenic differentiation. Furthermore, an injectable SC-Exos-loaded gelatin methacrylate hydrogel (SC-Exos/GelMA) targeting BMSCs was constructed. In vitro, SC-Exos/GelMA enabled sustained release of Exos and promoted BMSCs osteogenesis. In vivo, SC-Exos/GelMA downregulated TF expression via the miR-212-3p/TF axis, mitigated ferroptosis, restored iron homeostasis, accelerated angiogenesis/neurogenesis, and promoted bone regeneration. This study not only elucidated the role of the miR-212-3p/TF axis in the modulation of BMSCs iron homeostasis, but also constructed an injectable SC-Exos/GelMA hydrogel for bone regeneration, offering mechanistic insights and a translational therapeutic strategy for bone regeneration in clinic.

Keywords:  Bone marrow mesenchymal stem cells; Bone regeneration; Ferroptosis; Osteoporosis; Schwann cell-derived exosomes

DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.053
Bioact Mater. 2026 Nov;65 380-397

Bioengineered titanium implants functionalized with aptamer-valproic acid conjugates orchestrate macrophage programming and mesenchymal stem cell homing for improved osseointegration.

Danhe Sun, Quan Zhou, Xiaoling Guo, Hang Shi, Xiaoyan Wang, Xinkai Li, Zhihuang Zheng, Linfeng Zhong, Senhu Cao, Ruifan Shan, Zexu Su, Chufan Ma, Lingzhou Zhao.

  Conventional titanium implants often exhibit limited bioactivity, failing to adequately modulate the immune response and promote endogenous regeneration, which leads to suboptimal osseointegration. To address this, we developed a multifunctional implant (NTP/Apt-VPA) by conjugating Apt19s-an mesenchymal stem cell (MSC)-specific aptamer-with valproic acid (VPA), anchored onto a polydopamine-coated TiO2 nanotubular surface. The NTP/Apt-VPA implant demonstrated exceptional capabilities in scavenging reactive oxygen species, programming macrophages toward the regenerative M2 phenotype, and enhancing the recruitment and osteogenic differentiation of MSCs. Through comprehensive in vitro and in vivo assessments, as well as RNA sequencing analysis, we observed that the modified implant was associated with accelerated early inflammation resolution, enhanced stem cell homing, and activation of key osteogenic pathways, including PI3K/AKT and MAPK signaling. This study presents a bioengineering strategy that aims to synchronize immunomodulation with osteogenesis through an Apt19s-VPA conjugate, which may offer a promising platform for enhancing implant osseointegration.

Keywords:  Immunomodulation; Macrophage polarization; Mesenchymal stem cell homing; Osseointegration; Titanium implants

DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.055
Cartilage. 2026 Jun 16. 19476035261445874

Exosomal LINC01106 From PRP-Treated ADSCs Alleviates Chondrocyte Inflammatory Injury by Sponging miR-34a-5p to Upregulate SIRT1 Expression.

Xuan Zhang, Wentao Liu, Jinke Ren, Yangyi Yu, Zhongshi Xu.

  ObjectiveOsteoarthritis (OA) is characterized by progressive cartilage degeneration driven by inflammation-induced chondrocyte injury, while effective disease-modifying therapies are still lacking. Exosome-based cell-free approaches are emerging as promising alternatives, but their key molecular mediators remain incompletely defined.DesignAdipose-derived stem cells (ADSCs) were pretreated with platelet-rich plasma (PRP) to enhance exosomal function. Isolated exosomes were characterized, and LINC01106 expression was modulated by overexpression or knockdown. Interleukin (IL)-1β-stimulated chondrocytes were used to assess apoptosis, inflammatory cytokine secretion, oxidative stress, and extracellular matrix degradation. The LINC01106/miR-34a-5p/SIRT1 axis was examined using luciferase reporter assays, quantitative real-time polymerase chain reaction (PCR), Western blotting, and immunofluorescence.ResultsPRP pretreatment markedly increased LINC01106 enrichment in ADSC-derived exosomes. LINC01106-rich exosomes significantly reduced chondrocyte apoptosis, suppressed tumor necrosis factor-α (TNF-α) and IL-6 secretion, alleviated oxidative stress, and attenuated matrix metalloproteinase (MMP)-mediated matrix degradation under IL-1β stimulation. Mechanistically, LINC01106 acted as a competing endogenous RNA that sequestered miR-34a-5p, thereby restoring SIRT1 expression. Rescue experiments demonstrated that miR-34a-5p overexpression or SIRT1 silencing abolished these protective effects. In addition, LINC01106-enriched exosomes inhibited nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway activation in a SIRT1-dependent manner.ConclusionPRP-stimulated ADSC-derived exosomes confer potent chondroprotective effects through the LINC01106/miR-34a-5p/SIRT1 pathway, highlighting a promising cell-free therapeutic strategy for OA.

Keywords:  LINC01106; SIRT1; exosomes; miR-34a-5p; osteoarthritis; platelet-rich plasma

DOI:  https://doi.org/10.1177/19476035261445874
J Biomed Mater Res A. 2026 Jun;114(6): e70109

Reduced Hypotonic Exposure and Sequential Membrane Cholesterol Enrichment Limit Phosphatidylserine Externalization and Enhance Circulatory Retention of Erythrocyte-Derived Microparticles.

Shamima Zaman, Grant Swajian, Shiril Bhardwaj Iragavarapu, Md Tashdid Hossain Shoudho, Bahman Anvari.

  Erythrocyte-derived carriers have emerged as effective biomimetic platforms for the delivery of therapeutic and imaging cargos. However, clearance by the mononuclear phagocytic system (MPS) limits their utility. Towards development of standardized methods for increased bioavailability, we have developed an approach that lowers the externalization of phosphatidylserine (PS), a biomarker for MPS clearance, to the outer leaflet of the membrane. Specifically, this approach minimizes the hypotonic treatment of erythrocytes to a single cycle for depleting the hemoglobin while enriching the membrane bilayer with cholesterol during depletion, and in the subsequent cargo loading step, using indocyanine green (ICG), a fluorescent probe as an illustrative cargo. Using this strategy, PS externalization remains limited to ~16% and 9% of the carrier system with and without the encapsulated ICG, respectively, compared to ~46%-99% following multiple hypotonic cycles without cholesterol enrichment. Carriers engineered using this method exhibit significantly reduced macrophage uptake in vitro. In vivo biodistribution studies in healthy mice show ~2.7-fold increase in blood-associated fluorescence, and ~3.3-fold decrease in splenic accumulation after intravascular injection relative to carriers formed by multiple cycles of hypotonic treatment and without cholesterol enrichment. This method provides an effective approach to improve the circulatory retention of erythrocyte-based carriers.

Keywords:  biomimetic; cell‐based carriers; drug delivery; fluorescence; red blood cells

DOI:  https://doi.org/10.1002/jbm.a.70109
3 Biotech. 2026 Jul;16(7): 263

Evaluation of Biosynthesized Berberis vulgaris-loaded gold nanocomposites: in vitro cytotoxicity and anti-giardial efficacy against giardia intestinalis.

Qwait AlGabbani.

  Giardiasis is a common parasitic disease that remains a major global health concern, largely because of rising drug resistance and the adverse effects linked to existing therapeutic options. To address this urgent need for novel therapeutic strategies, we explored the potential of Berberis vulgaris, a traditionally recognized medicinal plant, and its biosynthesized gold nanocomposites (BV-AuNPs) as anti-giardial agents. Initially, a comprehensive phytochemical characterization of B. vulgaris root bark was performed, revealing a diverse spectrum of bioactive constituents, including phenolic compounds, flavonoids, and various volatile metabolites, which likely contribute to its established traditional medicinal applications. We then successfully developed BV-AuNPs using an environmentally friendly green synthesis approach. Our characterization studies, employing UV-Vis, FT-IR, and TEM, confirmed the successful formation of stable, predominantly spherical gold nanoparticles with an average size of 10 nm, indicating the plant extract's role in both reduction and stabilization. In our in vitro assessments, we observed that BV-AuNPs exhibited significantly enhanced antioxidant activity compared to the raw B. vulgaris extract. More critically, we evaluated their anti-giardial efficacy against Giardia intestinalis. Both the B. vulgaris extract and BV-AuNPs demonstrated dose-dependent mortality against G. intestinalis cysts and trophozoites. Notably, BV-AuNPs consistently showed superior efficacy, achieving 96.41% cyst mortality and 93.2% trophozoite mortality at 150 µg/mL, comparable to the efficacy of metronidazole at a much lower concentration (25 µg/mL). Furthermore, we extended our evaluation to an in vivo murine model. Here, BV-AuNPs significantly reduced fecal cyst counts by 72.2% and intestinal trophozoite load by an impressive 90%, surpassing the efficacy of the raw extract and demonstrating strong therapeutic potential. Our results demonstrate that the nano-formulation markedly enhances the anti-giardial activity of B. vulgaris, likely through improved bioavailability and targeted delivery of its bioactive compounds. These findings provide a foundation for developing a more effective and safer therapeutic strategy for giardiasis.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-026-04873-1.

Keywords:  Anti-giardial efficacy; Berberis vulgaris; Giardiasis; Gold Nanocomposites (AuNPs); Phytochemical analysis

DOI:  https://doi.org/10.1007/s13205-026-04873-1
Synth Syst Biotechnol. 2026 Dec;14 487-497

Progresses of transposon research in Saccharomyces cerevisiae.

Wenbo Lin, Yu Lv, Yuhao Zhang, Zhaoxia Jin, Linxia Liu, Dawei Zhang.

  Transposons are mobile genetic elements that have attracted sustained scientific interest since their discovery in maize, evolving into indispensable tools in genetic research. Saccharomyces cerevisiae serves as a preferred model for transposon studies, benefiting from a mature genetic manipulation system, a well-characterized genome, and cellular mechanisms that resemble those of higher organisms. This review summarizes recent advances and application strategies of transposons in S. cerevisiae. We begin by classifying transposons based on their transposition mechanisms, with a focus on representative systems including the Tn, hAT, Ty, piggyBac (PB), Tc1/mariner and CRISPR-associated transposon (CAST) families, detailing their molecular mechanisms. We further discuss the applications of endogenous and engineered transposons in yeast, address key challenges such as insertion bias and genomic instability, and summarize corresponding engineering strategies aimed at enhancing their efficiency and specificity. Our goal is to provide a roadmap for developing transposons into efficient, precise, and low-off-target genome-editing tools, thereby advancing the construction of yeast cell factories.

Keywords:  Metabolic engineering; Saccharomyces cerevisiae; Synthetic biology; Transposons

DOI:  https://doi.org/10.1016/j.synbio.2026.05.004
J Mater Chem B. 2026 Jun 10.

Extracellular vesicle-integrated gelatin sponges enhance angiogenesis and cell migration in wound healing.

Elif Conger-Onder, Sukru Ozturk, Naside Mangir, Alp Can, Kezban Ulubayram.

Wound healing remains a major global burden on healthcare systems. Extracellular vesicle (EV)-based therapies have emerged as promising cell-free approaches due to their ability to deliver bioactive cargo. However, their clinical transition is largely limited by the lack of effective delivery systems for preserving EV stability and bioactivity at the target site following administration. Herein, we present clinically relevant, biocompatible and biodegradable gelatin sponges (GS) as a functional biomaterial platform for EVs derived from rat bone-marrow mesenchymal stromal cells (rt-BM-MSCs). The GS was fabricated via glutaraldehyde crosslinking, followed by lyophilization, to obtain a stable and highly porous architecture suitable for EV loading. This intrinsic porous structure enabled efficient EV loading and incorporation within the scaffold. Biological function assays demonstrated that the incorporation of EVs into the GS preserved and supported their biological activities, particularly by enhancing keratinocyte migration, a key process in re-epithelialization during wound healing. The pro-angiogenic potential of the EV-integrated GS was further evaluated using ex vivo aortic ring and ex ovo chorioallantoic membrane (CAM) assays, which mimic microvascular sprouting and functional vascular network, respectively. In both models, the EV-integrated GS significantly promoted neovascularization, providing functional validation beyond conventional in vitro assays. These models provided physiologically relevant evidence of vascularization, a key process underlying granulation tissue formation and wound repair. Importantly, GS integration enhanced EV efficacy, indicating that the biomaterial microenvironment actively modulates EV bioactivity and improves angiogenic outcomes.

DOI: https://doi.org/10.1039/d6tb00705h
Trends Biotechnol. 2026 Jun 18. pii: S0167-7799(26)00238-6. [Epub ahead of print]

Engineered Bacillus subtilis to deliver dsRNA via extracellular vesicles against the H9N2 avian influenza virus.

Jiachen Liu, Yimeng Yang, Yichao Ma, Xinming Qin, Yaotang Wu, Shubin Li, Yunlei Cao, Jian Lin, Qian Yang.

  RNA interference (RNAi) is a potent antiviral approach, outperforming traditional pesticides and broad-spectrum drugs. Its use in animal disease control faces two challenges: inefficient target design relying on computer-predicted small-interfering RNAs (siRNAs) rather than virus-derived siRNAs (vsiRNAs), and the lack of cost-effective siRNA delivery systems. In this study, we address both limitations by engineering a probiotic Bacillus subtilis 168 strain, called the recombinant B. subtilis AAD (Anti-AIV-DsRNA, targeted AIV), that constitutively expresses vsiRNA-enriched dsRNA targeting the H9N2 avian influenza virus. Oral administration of AAD leads to the release of double-stranded RNA (dsRNA)-loaded extracellular vesicles (EVs), which efficiently reduce H9N2 viral loads and mitigate pathological lesions. Mechanistically, virus-derived dsRNA is processed by the enzyme Dicer into siRNAs, which then activate RNAi and interferon signaling, resulting in approximately a 70% reduction in viral burden. Overall, these findings demonstrate that integrating the probiotic properties of B. subtilis with EV-mediated dsRNA delivery constitutes a sustainable, effective, and residue-free antiviral strategy for animal disease.

Keywords:  Bacillus subtilis; H9N2; RNAi; extracellular vesicles

DOI:  https://doi.org/10.1016/j.tibtech.2026.05.025
Sci Rep. 2026 Jun 18.

Alkaline loading of extracellular vesicles produced from human neural stem cell-derived neurospheres enables CNS drug delivery.

Amar M Singh, Charles M White, Adeline Phillips, Logan P Crowe, Robert Marti, Morgan C Finnerty, Martonio Ponte Viana, William Antoniades, Michael G Bartlett, Viviana Martinez, Raymond Swetenburg, Steven L Stice.

  The blood brain barrier and blood tumor barrier (BBB and BTB, respectively) represent significant obstacles for the delivery of drugs to treat diseases of the central nervous system, such as brain cancers and neurodegenerative diseases. Extracellular vesicles (EVs) or exosomes have emerged as a new drug delivery vehicle for CNS diseases as they may penetrate the BBB/BTB and are less immunogenic than liposomal carriers. EVs derived from human neural stem cells (hNSC) provide additional benefits over other EV sources due to their increased homing capability to neural cells and demonstrated efficacy for treating stroke and traumatic brain injury in rodent models. However, the utilization of EVs from hNSC for drug delivery remains largely unexplored, due in part to difficulties in manufacturing capacity compared to traditional cell lines. Here, we report the development of a hNSC suspension neurosphere system for EV production and drug delivery. As proof of concept, doxorubicin was loaded into hNSC-EV, using a novel, high-efficiency alkaline passive loading method, and shown to be effective at inducing cytotoxicity in glioma cells in vitro and exhibiting higher BBB penetrance than doxorubicin-alone in vivo. These studies demonstrate the potential for hNSC-EV loaded doxorubicin as a therapeutic treatment for brain cancers such as glioblastoma, while also establishing hNSC-EVs as a drug-delivery vehicle for CNS diseases.

Keywords:  Alkaline loading; Blood–brain barrier; Doxorubicin; Drug delivery; Exosomes; Extracellular vesicles; Glioblastoma; Neural progenitor cells; Neural stem cells

DOI:  https://doi.org/10.1038/s41598-026-58290-8
Phytomedicine. 2026 Aug;pii: S0944-7113(26)00638-0. [Epub ahead of print]158 158407

A sustained-release sinomenine hydrogel targets microglial ferroptosis via Nrf2-hmox1 activation to alleviate diabetic peripheral neuropathy.

Ji Chen, Lin Zhu, Yangyuxi Chen, Yuan Liu, Wen Chen, Xinxin Liu, Pingsen Zhao, Fengrui Yang.

   BACKGROUND: Sinomenine (SIN), a bioactive alkaloid from Sinomenium acutum, possesses anti-inflammatory properties, but its efficacy against diabetic peripheral neuropathy (DPN) is limited by poor bioavailability and undefined mechanisms.
PURPOSE: This study aimed to evaluate the therapeutic effects and mechanism of a SIN-loaded hydrogel (Gel-SIN-M) in DPN.
METHODS: Gel-SIN-M was engineered via crosslinking for controlled SIN delivery. DPN mice received perineural Gel-SIN-M injections. Pain thresholds (von Frey) and motor coordination (gait analysis) were quantified. Intraepidermal nerve fiber density (IENFD), toluidine blue staining, and TEM analyses were used to assess structural recovery. Molecular markers (Nrf2, Hmox1, GPX4, ACSL4) were analyzed by qPCR/Western blot. Ferroptosis inhibition was confirmed in high-glucose-stimulated microglia and further evaluated using RSL3 or ML385 intervention.
RESULTS: Gel-SIN-M showed excellent biocompatibility and sustained drug release. Treatment significantly improved insulin levels, reduced blood glucose, and alleviated neuropathic pain and motor deficits in DPN mice. It decreased inflammation, restored neurite length, and enhanced nerve fiber density, axon diameter, and myelin thickness. Mechanistically, Gel-SIN-M upregulated Nrf2 and Hmox1, increased GPX4, reduced ACSL4 expression, and suppressed ferroptosis and Fe²⁺ accumulation in microglia. The Nrf2 inhibitor ML385 attenuated these protective effects, supporting the involvement of the Nrf2-Hmox1 axis.
CONCLUSION: This study developed a thermosensitive Gel-SIN-M hydrogel that enables sustained, localized drug release in diabetic neuropathic lesions. Gel-SIN-M markedly alleviated neuropathic pain and motor dysfunction in DPN mice through activation of the Nrf2-Hmox1 axis and inhibiting microglial ferroptosis. Importantly, this work is the first to identify microglial ferroptosis as a novel pathogenic mechanism driving DPN progression, and it suggests activation of the Nrf2-Hmox1 axis as a potential multi-target therapeutic strategy integrating antioxidative, anti-inflammatory, and antiferroptotic effects. These findings introduce a new conceptual framework and a promising biomaterial-based approach for the treatment of DPN.

Keywords:  Diabetic peripheral neuropathy; Erythroid 2-related factor 2-heme oxygenase 1 pathway; Ferroptosis; Microglia; Sinomenine

DOI:  https://doi.org/10.1016/j.phymed.2026.158407
Front Immunol. 2026 ;17 1864256

Chimeric antigen receptor technology: an emerging translational immunotherapy in nonneoplastic diseases.

Sijie Zhou, Yuan Li, Jiulu Zhao, Wang Zhan, Cheng Zhou, Yanqiang Zou, Xiaohan Li, Jikai Cui, Jie Wu, Jiahong Xia.

   Background: One of the most significant recent advancements in cancer immunotherapy is the development of chimeric antigen receptor (CAR) technology. More recently, this approach has been gradually modified for the research associated with various treatment-resistant nonneoplastic diseases by engineering immune cells to provide precise targeting.
Results: This narrative review discusses two primary therapeutic approaches the use of CAR technology in the treatment of nonneoplastic diseases. One strategy involves the elimination of specific pathogenic cell populations. Specifically, by engineering T cells, macrophages, or natural killer (NK) cells, pathogenic cells can be eliminated in autoimmune disorders, infectious diseases, and fibrotic lesions. The second approach aims to restore immune homeostasis by using engineered regulatory T cells (Tregs) to control augmented immune effector responses. This strategy has been shown to promote transplant tolerance and has therapeutic potential for inflammatory bowel disease and type 1 diabetes. Furthermore, this review addresses major issues concerning the persistence, safety, and manufacturing accessibility of CAR cells and discusses some emerging technological approaches that could be used for focused refinements of this technology.
Conclusions: The precision medicine platform for CAR technology has advanced beyond oncology by integrating targeted cell destruction with the management of immune homeostasis. As future possibilities with frontier cell engineering and interdisciplinary approaches are explored, CAR cell therapy is likely to evolve into a more adaptable, refined, and clinically viable immunotherapy technology, with its therapeutic potential expanded to a broad range of diseases.

Keywords:  chimeric antigen receptor (CAR) technology; engineered immune cells; immunotherapy; nonneoplastic diseases; precision targeting

DOI:  https://doi.org/10.3389/fimmu.2026.1864256
Mol Cell Probes. 2026 Jun 17. pii: S0890-8508(26)00016-2. [Epub ahead of print]89 102076

Harnessing serum exosomal snoRNAs: A novel liquid biopsy approach for NSCLC diagnosis.

Jianguo Hong, Yunwen Wang, Tingchao Wu, Zhijun Zhang, Kangyu Wang.

   BACKGROUND: The low early diagnostic efficacy of non-small cell lung cancer (NSCLC) is a key contributor to its high mortality rate, and small nucleolar RNAs (snoRNAs) in serum exosomes can serve as a beneficial liquid biopsy approach for the early diagnosis of NSCLC.
METHODS: Exosomes were isolated from collected serum; their morphology was imaged using transmission electron microscopy (TEM); particle size was measured using a particle size analyzer; and the expression of exosomal membrane proteins was identified using Western blot. Gene chips were used to screen for differentially expressed snoRNAs in exosomes, which were further validated by quantitative PCR (qPCR). The area under the receiver operating characteristic (ROC) curve (AUC) was used to estimate their diagnostic performance for NSCLC. Their biological functions in NSCLC were evaluated using an in vitro study.
RESULTS: A series of exosome characterization experiments confirmed successful exosome extraction. Microarray and qPCR analyses revealed that serum exosomal snoRNAs (AC092799.1-201 and AC009408.1-201) were significantly upregulated in individuals with NSCLC. When combined with CEA and CYFRA21-1, these two exosomal snoRNAs achieved diagnostic efficacy of 0.948 and early diagnostic efficacy of 0.917. Cell experiments confirmed that AC092799.1-201 is related to rapid proliferation and high invasiveness of tumor cells.
CONCLUSION: Exosomal snoRNAs AC092799.1-201 and AC009408.1-201, merged with CEA and CYFRA21-1, can serve as a novel liquid biopsy approach for the early diagnosis of NSCLC.

Keywords:  Early diagnosis; Exosomes; NSCLC; snoRNA

DOI:  https://doi.org/10.1016/j.mcp.2026.102076
J Biomater Sci Polym Ed. 2026 Jun 13. 1-24

Emerging trends of multifunctional biomaterial scaffolds for targeted antibacterial therapy and enhanced bone regeneration in osteomyelitis.

Jayesh S Bhamare, Ginpreet Kaur.

  A biocompatible scaffolds repairs bone defects with anti-infection properties in the treatment of osteomyelitis. Osteomyelitis is a severe infection of bone marrow, caused by Staphylococcus aureus, leading to inflammation and bone destruction. This condition manifests either acutely or chronically, influenced by factors such as diabetes-related vascular insufficiency, trauma, and surgical interventions. It involves bacterial colonisation of bone tissue, activation of the immune response, biofilm formation, and invasion of the osteocytes' lacuno-canalicular network, contributing to chronic infection. Current treatments face limitations due to systemic antibiotic inefficiency and the need for invasive procedures. Scaffolds have emerged as a promising solution for osteomyelitis management, offering structural support and localised delivery of antimicrobial agents. These biocompatible materials, ranging from natural polymers like collagen and chitosan to synthetic biodegradable materials such as Poly(lactic-co-glycolic acid), Polylactic acid, and Fibrin silk, address infection while promoting bone regeneration. The review highlights the potential of scaffolds-based strategies in treating osteomyelitis, focusing on their ability to overcome biofilm resistance and promote tissue repair. Novel antibiotic formulations for localised delivery, and combination therapies integrating osteogenic agents with antimicrobial drugs are helping in advanced therapeutic strategies. These address current challenges in clinical translation by optimising scaffold design and improving stability.

Keywords:  Biomaterial; Bone tissue engineering; Nanocomposite; antimicrobial; osteomyelitis; scaffolds

DOI:  https://doi.org/10.1080/09205063.2026.2685398
ACS Omega. 2026 Jun 09. 11(22): 31820-31830

The Application of Photodynamics Therapy and Tumor Tracing by IR820-Based Nanoparticles Targeting Cancer Cells.

Dezhi Tan, Yu Wang, Caihua Xu, Ying Wang.

IR820 is a molecule that emits intense fluorescence in the near-infrared (750-1700 nm) region and can efficiently absorb near-infrared light, converting it into thermal energy, making it powerful in tumor photothermal therapy. However, the nonspecific biodistribution of free IR820 in vivo and the limited tissue penetration depth of light reduce its overall therapeutic efficacy, highlighting the need for further optimization strategies. To address this problem, researchers have engineered IR820 with various nanomaterials to construct nanoplatforms that enable targeted delivery to tumor cells. This review summarizes the applications of IR820-based nanoplatforms in cancer photothermal and photodynamic therapies, with a particular focus on their therapeutic advantages and the current challenges.

DOI: https://doi.org/10.1021/acsomega.5c11050