bims-engexo 2025-11-23 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–11–23
eleven papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Epigenetic silencing of MSTN via m6A modification underlies the renoprotective effects of engineered MSC exosomes with RBM15 depletion in diabetic nephropathy.
Targeted engineered exosomes alleviate myocardial infarction injury by enhancing angiogenesis and improving mitochondrial function.
Exosome-mediated macrophage regulation in abdominal aortic aneurysm treatment.
Mesenchymal stem cell-derived exosomes as cell-free therapeutics: mechanistic insights and engineering strategies for liver disease treatment.
Biohybrid nanocarriers for targeted drug delivery by integrating biological interfaces with synthetic platforms for site-specific therapeutics.
Engineered mesenchymal stem cell-derived exosomes: A revolutionary approach to unlocking liver disease treatment.
Engineered Extracellular Vesicles for Treatment of Inflammatory Diseases.
Engineered reconstructed extracellular vesicles coloaded with Astragaloside IV/Paeoniflorin improve cerebral ischemia/reperfusion injurybyinhibiting the inflammatory response.
Innovative Strategy for Enhanced Delivery of Anti-Fibrotic miR-150 via PDGFR-Targeted Exosomes for Fibrosis Treatment.
Engineered extracellular vesicles demonstrate altered endocytosis and biodistribution and have superior oral siRNA delivery efficiency compared to lipid nanoparticles.
Recent advances in PDEVs as nanocarriers for drug delivery: loading techniques, engineering strategies and future directions.

Funct Integr Genomics. 2025 Nov 17. 25(1): 244

Epigenetic silencing of MSTN via m6A modification underlies the renoprotective effects of engineered MSC exosomes with RBM15 depletion in diabetic nephropathy.

Qianlan Dong, Longhao Dong, Yanting Zhu, Xiaoming Wang, Xiaohui Yan.

  Diabetic nephropathy (DN) is a leading complication of diabetes mellitus. Engineered exosomes have shown promise in disease treatment by enabling targeted cargo delivery. RNA-binding motif protein 15 (RBM15) accelerates the progression of DN. This study developed siRBM15-loaded exosomes and evaluated their therapeutic efficacy and mechanisms. Exosomes were isolated from human umbilical cord MSCs (hucMSCs) and loaded with siRBM15 (siRBM15-Exo) by electroporation. Human glomerular mesangial cells (HGMCs) were exposed to high glucose (HG). A rat model of DN was generated by streptozotocin induction. The effects on cell pathological responses were evaluated by detecting α-SMA and collagen IV expression, TNF-α and IL-1β levels, ROS and MDA levels, SOD activity, the percentage of SA-β-gal positive cells, and senescence-associated factors p53 and p21. The impact on DN rats was assessed by measuring pathological changes and inflammation. Myostatin (MSTN) and RBM15 were overexpressed in DN kidneys and HG-stimulated HGMCs. MSTN depletion reduced the production of the related markers of fibrosis, inflammation, oxidative stress, and senescence in HG-stimulated HGMCs. Mechanistically, RBM15 stabilized MSTN mRNA via m6A methylation. Reintroducing MSTN reversed these protective effects of RBM15 silencing on HG-induced pathological responses in HGMCs. Furthermore, siRBM15-Exo attenuated HG-induced fibrotic, inflammatory, oxidative, and senescent responses in HGMCs and mitigated inflammation and pathological changes in DN rats. SiRBM15-Exo downregulated MSTN in HG-stimulated HGMCs. Our study shows that the siRBM15-Exo effectively suppress MSTN expression to alleviate DN progression, providing promising translational potential for DN therapy.

Keywords:  Diabetic nephropathy; Engineered exosomes; M6A methylation; MSCs; SiRBM15

DOI:  https://doi.org/10.1007/s10142-025-01746-3
J Control Release. 2025 Nov 14. pii: S0168-3659(25)01018-1. [Epub ahead of print] 114404

Targeted engineered exosomes alleviate myocardial infarction injury by enhancing angiogenesis and improving mitochondrial function.

Haixia Luo, Kexin Wang, Yan Zhang, Tiantian Li, Xiaojie Jia, Renqian Feng, Ran Zhao, Rui Yu, Lang Hu, Mingming Zhang, Bingchao Qi, Yan Li.

  Myocardial infarction (MI) remains a leading cause of global mortality, where acute ischemic injury and chronic cardiomyocyte dysfunction are pathological mechanisms leading to heart failure (HF). Current therapies fail to effectively halt this progression. Although VegfA delivery shows potential for revascularization, its clinical translation is limited by inefficient delivery systems. Exosomes, as emerging nanocarriers, hold promise but suffer from poor targeting. Here, a dual mRNA-loaded exosome platment (ExoIC-LNV) for synergistic therapy is developed. The exosome is functionally designed with ischemic myocardium targeting peptide (IMTP) and Connexin 43 (Cx43) to accumulate at the ischemic region. Meanwhile, ExoIC-LNV contains VegfA mRNA and Ndufs1 mRNA, based on the binding properties of L7Ae. The results demonstrate that ExoIC-LNV achieve significantly higher enrichment in ischemic tissue compared to single targeted modified exosomes. The Ndufs1-loaded exosomes improve mitochondrial function in hypoxic cardiomyocytes, and the VefgA-loaded exosomes promote angiogenesis in ischemic tissue. ExoIC-LNV loaded with dual mRNAs exhibit superior mitochondrial improvement while promoting angiogenesis, resulting in better cardiac function improvement through dual-pathway modulation after MI. Through multiple tail vein injections, the benefical proteins accumulate in the ischemic area, providing better prospects for clinical translation. This study proposes a targeted exosome-based strategy for combating pathological remodeling in MI and represents a possible approach for HF prevention.

Keywords:  Angiogenesis; Exosomes; Mitochondria; Myocardial infraction

DOI:  https://doi.org/10.1016/j.jconrel.2025.114404
Life Sci. 2025 Nov 17. pii: S0024-3205(25)00724-6. [Epub ahead of print] 124088

Exosome-mediated macrophage regulation in abdominal aortic aneurysm treatment.

Hanxun He, Hao Liu, Peiwen Yang, Yufan Zhou, Jiaqi Huang, Ping Ye, Jiahong Xia.

  Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by the irreversible dilatation of the aortic wall. AAA progression is closely linked to an imbalance in macrophage polarization, chronic inflammation, and the degradation of the extracellular matrix (ECM). This review expounded on the potential role of exosomes, as natural bioactive carriers, in modulating macrophage polarization, metabolic reprogramming, and pyroptosis by delivering various biomolecules, including non-coding RNAs (ncRNAs), proteins, and lipids, thereby influencing the pathogenesis of AAA. Exosomes facilitate intercellular communication in AAA by transferring bioactive molecules that potentially influence macrophage polarization and inflammatory responses through various mechanisms. These include the inhibition of NLRP3 inflammasome activation, modulation of the balance between glycolysis and oxidative phosphorylation, as well as targeting key signaling pathways such as PARP-1/PP-1α/JNK/c-Jun and TSC2-mTOR-AKT. Moreover, engineered exosomes, such as those modified with targeting peptides, magnetic nano-drug delivery systems, and hydrogel-based sustained-release platforms, are currently being investigated to improve lesion targeting and therapeutic durability, thereby offering a promising multidimensional intervention strategy for AAA treatment. However, the clinical application of exosomes continues to encounter several challenges, including the absence of standardized production protocols, obstacles in large-scale preparation, and inadequate safety verification. Future research should prioritize a comprehensive analysis of the exosome-macrophage interaction network, the development of advanced delivery systems, and the validation of preclinical efficacy. These efforts are indeed crucial for advancing the translational application of exosome-based immunomodulatory strategies in the treatment of AAA.

Keywords:  Abdominal aortic aneurysm; Engineered exosomes; Exosome-mediated modulation; Exosomes; Macrophage; Therapeutic strategy

DOI:  https://doi.org/10.1016/j.lfs.2025.124088
Stem Cell Res Ther. 2025 Nov 20. 16(1): 652

Mesenchymal stem cell-derived exosomes as cell-free therapeutics: mechanistic insights and engineering strategies for liver disease treatment.

Shihang Yu, Defu Kong, Beike Lu, Yixiao Pan, Zhaokai Zeng, Yuan Fu, Zhicong Zhao, Kang He, Ruqi Tang, Qiang Xia.

  Liver diseases pose a global health crisis, with liver transplantation remaining the only definitive therapy yet constrained by donor scarcity and complications. Mesenchymal stem cells (MSCs), emerging as stromal cells with immunomodulatory and regenerative capacities, face translational challenges. By contrast, MSC-derived exosomes (MSC-Exos) offer a cell-free approach with lower immunogenicity, minimal tumorigenic risk, and intrinsic hepatic tropism, mediating intercellular communication via protein and microRNA (miRNAs) cargo. To provide a focused synthesis, this review establishes a unified four-pillar framework of MSC-Exos mechanisms across liver pathologies, including (i) maintaining immunological-stromal homeostasis, (ii) reprogramming metabolic circuitry, (iii) determining cell fate, and (iv) intercepting oncogenic signaling. We further discuss advances in engineered MSC-Exos from preparation and application, aiming at enabling precision delivery and the mechanism-to-translation process. While MSC-Exos represent a transformative frontier in hepatology, addressing heterogeneity, scalable production, and cargo standardization remains critical to accelerate clinical translation.

Keywords:  Cell-free therapeutics; Engineered exosomes; Exosomal miRNA delivery; Immunomodulation; Liver disease; Mechanistic insight; Mesenchymal stem cell-derived exosome; Metabolic reprogramming; Regeneration

DOI:  https://doi.org/10.1186/s13287-025-04747-y
Int J Pharm. 2025 Nov 15. pii: S0378-5173(25)01237-2. [Epub ahead of print]687 126400

Biohybrid nanocarriers for targeted drug delivery by integrating biological interfaces with synthetic platforms for site-specific therapeutics.

Sathvik Chennamsetty, Mahesha Keerikkadu, Akshay Shetty, Pragathi Devanand Bangera, Vamshi Krishna Tippavajhala, Mahalaxmi Rathnanand.

  Biohybrid nanocarriers (BHNs) are a fast-moving new horizon in targeted drug delivery, merging the biological complexity of naturally occurring systems like exosomes, bacterial outer membrane vesicles, red blood cell membranes, and other cell-derived vesicles with the structural versatility and functional adaptability of synthetic nanomaterials. This combined strength allows BHNs to be endowed with enhanced biocompatibility, extended systemic circulation, minimized immunogenicity, and highly specific targeting properties. The objective of this review is to achieve a detailed and critical overview of recent developments in BHN platforms, highlighting their architectural diversity, drug-loading strategies, functional mechanisms, and wide therapeutic utility. BHNs are gaining attention for their promise in the therapy of cancer, neurodegenerative disorders, infectious diseases, and in next-generation vaccine delivery. RNA and protein delivery engineered exosomes, immune evasion, homotypic targeting cell membrane-coated nanoparticles, and smart hydrogels for responsive and localized drug release. These systems also provide multifunctionality through the co-delivery of therapeutic and imaging probes, facilitating in vivo tracking and theranostic applications. Their biomimetic design facilitates tissue regeneration, immune modulation, and better pharmacokinetics, with customizable platforms available for patient-specific therapy. The combination of biologic and synthetic components in BHNs is of transformative value for shaping safer, wiser, and more powerful nanomedicine approaches to personalized healthcare.

Keywords:  Biohybrid nanocarriers; Biomimetic; Cell membranes; Exosomes; Targeting ligand

DOI:  https://doi.org/10.1016/j.ijpharm.2025.126400
Biochem Biophys Rep. 2025 Dec;44 102313

Engineered mesenchymal stem cell-derived exosomes: A revolutionary approach to unlocking liver disease treatment.

Amir Hossein Kheirkhah, Mohsen Sheykhhasan, Faezeh Hosseinzadeh, Leyla Fath-Bayati.

  Exosomes, a specific type of extracellular vesicle with diameters ranging from 30 to 150 nm, play a vital role in coordinating various physiological and pathological processes through direct cell-to-cell communication. These vesicles transport a diverse range of molecules, including proteins, mRNAs, miRNAs, and lipids, that originate from parent cells. Exosomes are released by nearly all cell types, including mesenchymal stem cells (MSCs), and possess significant potential due to their regenerative and immunomodulatory properties. In the context of liver disease treatment, these capabilities offer hope. Despite their limited lifespan in the bloodstream and suboptimal targeting efficiency, researchers are exploring the potential of modifying MSC-derived exosomes through genetic or chemical means. This article highlights the promising characteristics and applications of MSC-derived exosomes, presenting new perspectives on the latest advancements in exosome engineering for liver regeneration and therapy.

Keywords:  Exosome; Liver; Mesenchymal stem cells; Regeneration

DOI:  https://doi.org/10.1016/j.bbrep.2025.102313
Mol Biotechnol. 2025 Nov 18.

Engineered Extracellular Vesicles for Treatment of Inflammatory Diseases.

Yiran Lu, Shizhi Wang, Bingjia Yu, Xiuting Li.

  Inflammation-related disorders constitute a major global health challenge, with annual incidence exceeding tens of millions of cases and economic losses surpassing hundreds of billions USD. These burdens significantly impact both healthcare systems and socioeconomic development. Current clinical therapies are limited by suboptimal efficacy, which poses health risks to patients and underscores the demand for innovative therapeutic strategies. Emerging evidence demonstrates that extracellular vesicles (EVs) exhibit significant therapeutic advantages over conventional pharmacological interventions in managing inflammatory disorders. Native EVs possess inherent advantages including superior biocompatibility, structural integrity, and unique biological barrier penetration capacities, positioning them as promising therapeutic agents for inflammatory conditions. Engineered EVs can be functionalized with targeted delivery systems to transport bioactive components, such as miRNAs and proteins, enabling precise modulation of inflammatory signaling pathways. This approach enhances therapeutic efficacy, shortens treatment duration, reduces morbidity rates, and decreases healthcare costs. This review examines the therapeutic potential of EVs in inflammatory diseases and summarizes recent advances in their application to specific inflammatory disorders. We discuss the clinical translation challenges of EVs and highlight their prospects for inflammatory disease therapeutics.

Keywords:  Drug delivery; Engineered extracellular vesicles; Inflammation; Targeting; Therapeutics

DOI:  https://doi.org/10.1007/s12033-025-01528-z
Colloids Surf B Biointerfaces. 2025 Nov 10. pii: S0927-7765(25)00774-X. [Epub ahead of print]258 115267

Engineered reconstructed extracellular vesicles coloaded with Astragaloside IV/Paeoniflorin improve cerebral ischemia/reperfusion injurybyinhibiting the inflammatory response.

Long Chen, Meiling Tang, Jiaxiang Zou, Jingyuan Mo, Yingli Gan, Xingli Wen, Pengcheng Wang, Zai Liu, Lisheng Wang.

  The method of nourishing qi and activating blood circulation is a key approach in traditional Chinese medicine for treating stroke. The combination of Astragaloside IV (qi-nourishing) and Paeoniflorin (blood-activating) in the BuYang HuanWu Decoction can enhance its therapeutic effects. Extracellular vesicles offer several advantages, including low immunogenicity, biodegradability, and the ability to cross the blood-brain barrier, making them ideal carriers for drug delivery. In this study, astragaloside IV and paeoniflorin were co-loaded into extracellular vesicles derived from milk using ultrasound, and RVG29 peptide was modified on their surface through hydrophobic insertion to achieve targeted delivery to the brain lesion area. Cell and small animal imaging experiments confirmed that these engineered reconstructed extracellular vesicles possess excellent brain-targeting capabilities. In the mouse model of cerebral artery occlusion/reperfusion, this co-delivery system significantly suppressed inflammation and improved brain injury, providing a new strategy for treating cerebral ischemia and demonstrating promising application prospects.

Keywords:  Astragaloside IV/Paeoniflorin; Cerebral ischemia; Drug delivery; Reconstructed extracellular vesicles

DOI:  https://doi.org/10.1016/j.colsurfb.2025.115267
J Korean Med Sci. 2025 Nov 17. 40(44): e294

Innovative Strategy for Enhanced Delivery of Anti-Fibrotic miR-150 via PDGFR-Targeted Exosomes for Fibrosis Treatment.

Tae Ho Hong, Jung Hyun Park, Ha-Eun Hong, Ho Joong Choi, Ok-Hee Kim, Say-June Kim.

   BACKGROUND: Fibrosis, caused by hepatic stellate cell (HSC) activation and resulting in extracellular matrix accumulation, cirrhosis, and ultimately liver failure, remains a critical challenge. Recent advances in exosome-based drug delivery systems offer an innovative approach by specifically targeting activated HSCs to combat fibrotic diseases. This study evaluated the anti-fibrotic potential of miR-150-loaded exosomes engineered with platelet-derived growth factor receptor (PDGFR)-targeting peptides for precise delivery to activated HSCs.
METHODS: Adipose-derived stem cells were genetically engineered to express PDGFR-targeting peptides via pDisplay vectors, resulting in the production of targeted exosomes (tEx). Subsequently, miR-150 was loaded into the targeted exosomes, termed tEx. In vitro and in vivo studies were conducted using a thioacetamide-induced liver fibrosis model.
RESULTS: Either real-time polymerase chain reaction or western blot analysis demonstrated that tEx significantly reduced fibrotic markers, including alpha-smooth muscle actin, collagen type I alpha 1 chain, and transforming growth factor beta 1, both in vitro and in vivo. Western blotting showed a 40% decrease in collagen deposition, while enzyme-linked immunosorbent assay indicated a 30% reduction in serum liver enzyme levels (aspartate transaminase and alanine aminotransferase) compared to controls. Immunohistochemical analysis demonstrated that tEx significantly reduced fibrosis markers and collagen deposition in liver tissues compared to controls, highlighting their strong anti-fibrotic and anti-inflammatory potential (P < 0.05).
CONCLUSION: The findings highlight the potential of PDGFR-tEx for efficient miR-150 delivery, demonstrating improved therapeutic efficacy with reduced systemic toxicity. This targeted approach may offer a more precise and effective treatment for liver fibrosis, surpassing conventional methods.

Keywords:  Adipose-Derived Stem Cells; Exosomes; Liver Fibrosis; PDGFR-Targeted Peptide; miR-150

DOI:  https://doi.org/10.3346/jkms.2025.40.e294
Int J Pharm X. 2025 Dec;10 100428

Engineered extracellular vesicles demonstrate altered endocytosis and biodistribution and have superior oral siRNA delivery efficiency compared to lipid nanoparticles.

Ning Ding, Armond Daci, Vanesa Krasniqi, Rachel Butler, Alan Goddard, Qing Guo, Yunyue Zhang, Jizhou Zhong, K L Andrew Chan, Maya Thanou, Driton Vllasaliu.

  Oral administration of RNA therapeutics remains a major unsolved challenge due to currently insurmountable biological barriers. Extracellular vesicles (EVs) are natural carriers capable of traversing the intestinal barrier, but inefficient RNA loading into EVs in general severely limits the application of EVs for RNA delivery. Here, we utilize a microfluidic engineering platform to generate milk-derived EV-lipid nanoparticle (EV-LNP) hybrids for oral delivery of RNA. The process produced uniform nanoparticles (133 nm, polydispersity index 0.19) with >45 % dual-positive fusion efficiency, significantly outperforming freeze-thaw hybridization. Compared to conventional LNPs, EV-LNP hybrids exhibited lower cytotoxicity, altered epithelial uptake pathways, and markedly improved intestinal epithelial transport. Importantly, the hybrids retained gene-silencing efficacy following exposure to simulated intestinal fluids, achieving 40-60 % glyceraldehyde 3-phosphate dehydrogenase knockdown in Caco-2 cells, which was superior to LNPs. Oral gavage in mice revealed preferential colonic accumulation of EV-LNP hybrids compared to native EVs or LNPs, indicating strong potential for local RNA therapy in gut diseases such as colitis. Collectively, this study establishes a scalable, bioinspired delivery platform that addresses key translational barriers for oral RNA therapeutics and enables targeted delivery to the colon.

Keywords:  EV-LNP hybrids; Extracellular vesicles (EVs); Oral RNA therapy; RNA delivery; siRNA delivery

DOI:  https://doi.org/10.1016/j.ijpx.2025.100428
Expert Opin Drug Deliv. 2025 Nov 20.

Recent advances in PDEVs as nanocarriers for drug delivery: loading techniques, engineering strategies and future directions.

Bharathipriya Rajasekaran, Kai-Jiun Lo, Min-Hsiung Pan.

   INTRODUCTION: Plant-derived extracellular vesicles (PDEVs) have emerged as natural nanocarriers with promising applications in drug delivery and precision medicine. Secreted by plant cells, PDEVs facilitate intercellular communication by transporting metabolites. Unlike conventional liposomes and mammalian-derived EVs, PDEVs demonstrate excellent biocompatibility, stability, and the ability to cross biological barriers without inducing inflammatory or cytotoxic effects. Their capacity to encapsulate both hydrophilic and hydrophobic therapeutic agents highlight their versatility as targeted delivery platforms.
AREAS COVERED: This review summarizes PDEV biogenesis in comparison with mammalian-derived EVs and emphasizes characterization techniques and the role of lipid components in drug delivery efficacy. Drug loading strategies are critically examined with respect to their efficiency, advantages, and limitations. Advances in engineering, including surface modification and hybrid vesicle formation, are discussed to enhance targeting precision, circulation stability, and controlled drug release. Therapeutic potential and synergetic application in disease prevention and management are evaluated, alongside key considerations such as storage stability, current limitations, and opportunities for clinical translation.
EXPERT OPINION: PDEVs represents a promising platform for drug delivery and precision medicine. Although large-scale production, standardization and long-term stability remain challenges, recent innovations in loading strategies and engineering approaches demonstrate significant potential to overcome these barriers and accelerate clinical translation.

Keywords:  Plant-derived extracellular vesicles; drug loading; engineered EVs; hybrid vesicles; targeted drug delivery

DOI:  https://doi.org/10.1080/17425247.2025.2593981