{"title":"Therapeutic mechanistic framework of mesenchymal stem cell-derived extracellular vesicles in neurodegenerative diseases.","authors":"Gunjan Bawne, Magdalena J Lorenowicz","doi":"10.20517/evcna.2026.54","DOIUrl":"10.20517/evcna.2026.54","url":null,"abstract":"<p><p>Neurodegenerative diseases are a spectrum of progressive disorders unified by chronic neuroinflammation, oxidative and mitochondrial stress, and accumulation of misfolded proteins that ultimately drive neuronal dysfunction and loss. Despite recurring convergence on these pathogenic processes, therapeutic progress has remained limited, underscoring the need for interventions capable of targeting convergent pathogenic pathways rather than single downstream features. Mesenchymal stromal/stem cells (MSCs) have emerged as promising therapeutic candidates through their paracrine actions that modulate inflammatory and cellular stress responses within the nervous system. Increasing evidence indicates that extracellular vesicles released by MSCs (MSC-EVs) are key mediators of these effects, transferring regulatory RNAs, lipids, and proteins that reprogram recipient cells, attenuate neuroinflammatory cascades, and support neuronal survival. MSC-EVs can recapitulate key therapeutic mechanisms of their parent cells and may offer potential advantages in safety, scalability, and delivery across the blood-brain barrier. While MSC-EVs are promising candidates for treating these diseases, the molecular mechanisms underlying their effects are still emerging. In this review, we synthesise evidence from experimental models to develop a mechanistic framework describing how MSC-EVs modulate interconnected regulatory modules that shape neuroinflammation with blood-brain barrier dysfunction, oxidative and mitochondrial stress, and dysregulated proteostasis with loss of neurotrophic support. We further discuss how this modular perspective may inform strategies to mitigate infection-associated neurodegenerative trajectories, with particular attention to post-SARS-CoV-2 neurological sequelae. By integrating these mechanistic insights, this review provides a conceptual foundation for the rational optimisation and bioengineering of MSC-EV-based therapies targeting convergent regulatory pathways in neurodegeneration.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1653-1680"},"PeriodicalIF":8.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yunwei Wang, Qingchen Meng, Hui Li, Bonan Zhang, Dan Xing
{"title":"Artificial intelligence for extracellular vesicle engineering and therapeutic design.","authors":"Yunwei Wang, Qingchen Meng, Hui Li, Bonan Zhang, Dan Xing","doi":"10.20517/evcna.2026.159","DOIUrl":"10.20517/evcna.2026.159","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are promising platforms for next-generation drug delivery and regenerative therapeutics, yet biological heterogeneity, limited targeting specificity, variable cargo composition, and continued reliance on empirical optimization hinder clinical translation. Artificial intelligence (AI) offers new opportunities to make EV engineering more predictive and data-driven. Building on prior work in AI-assisted EV delivery and emerging virtual-EV modeling, this review presents an evidence-aware, multiscale framework that integrates parental-cell programming, vesicle design, recipient-system modeling, and experimental feedback. At the source level, AI virtual cells (AIVCs) may help predict how perturbations to parental cells influence EV biogenesis and composition. At the vesicle level, AI-guided approaches may support cargo prioritization, surface engineering, and loading optimization. At the recipient level, digital twin models could help simulate EV uptake, intracellular trafficking, microenvironmental interactions, and downstream therapeutic responses. These components may ultimately be integrated with experimental validation into iterative design-test-refinement workflows. Importantly, this review distinguishes direct EV-specific evidence from technologies transferable from adjacent fields and concepts that remain prospective. By defining these evidence boundaries and linking them to key challenges in data quality, model interpretability, manufacturing, and validation, this framework provides a practical roadmap for advancing AI-enabled EV therapeutics from conceptual modeling to testable, translationally relevant engineering strategies.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1625-1652"},"PeriodicalIF":8.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qingping Xi, Siyuan Wang, Qiongling Shi, Hui Wang, Ping Sun, Yan Jin, Yang Ma
{"title":"Emerging roles of plant-derived extracellular vesicles in the management of dental diseases.","authors":"Qingping Xi, Siyuan Wang, Qiongling Shi, Hui Wang, Ping Sun, Yan Jin, Yang Ma","doi":"10.20517/evcna.2026.145","DOIUrl":"10.20517/evcna.2026.145","url":null,"abstract":"<p><p>Dental diseases, including dental caries, pulpitis, and periodontitis, can cause pain and tooth loss, compromising mastication, speech, aesthetics, and quality of life. These diseases have also been associated with systemic disorders, including Alzheimer's disease. Conventional interventions, such as restorative procedures, root canal treatment, and periodontal scaling, have inherent limitations, underscoring the clinical need for novel therapeutic strategies. Plant-derived extracellular vesicles (PDEVs) have recently attracted considerable attention owing to their wide availability, cost-effectiveness, favourable biosafety profile, and capacity to mediate cross-kingdom communication. PDEVs exert diverse biological effects, including antimicrobial, anti-inflammatory, immunomodulatory, and tissue-regenerative activities. For example, ginger-derived PDEVs suppress the growth and virulence of <i>Porphyromonas gingivalis</i> through their lipid and miRNA cargoes, thereby alleviating periodontitis in mice. Given that effective dental therapy requires antimicrobial action, anti-inflammatory effects, immunomodulation, and tissue regeneration, PDEVs are promising therapeutic modalities. This review summarises the isolation, characterisation, composition, and biological functions of PDEVs, and discusses their potential applications in the management of dental diseases.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1600-1624"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genevieve C Sparagna, Christina M Coughlan, Hailey L Chapman, Sydney R Shuff, Ashley E Pietra, Benjamin J Kopecky, Alicia J Chapman, Eva M Medina, Anthony J Saviola, Kathryn C Chatfield, Shelley D Miyamoto, Anastacia M Garcia
{"title":"Region-specific human cardiac extracellular vesicles differentially regulate mitochondrial function.","authors":"Genevieve C Sparagna, Christina M Coughlan, Hailey L Chapman, Sydney R Shuff, Ashley E Pietra, Benjamin J Kopecky, Alicia J Chapman, Eva M Medina, Anthony J Saviola, Kathryn C Chatfield, Shelley D Miyamoto, Anastacia M Garcia","doi":"10.20517/evcna.2026.58","DOIUrl":"10.20517/evcna.2026.58","url":null,"abstract":"<p><p><b>Aim:</b> The human heart contains two major mitochondrial subtypes, <i>subsarcolemmal (SSL)</i>, fueling surface ion channels, and <i>interfibrillar (IF)</i>, fueling interior contractile machinery. This study investigated whether the distinct extracellular vesicles (EVs) that we determined to be associated with these regions could influence cardiac energetics. <b>Methods:</b> Following mitochondrial extraction, Subsarcolemmal Heart Extracellular Vesicles (SHEVs) and Interfibrillar Heart Extracellular Vesicles (IHEVs) were extracted from nonfailing human left ventricular lysates using precipitation-based methods. We characterized these EVs by size, proteomic profile, phospholipid content, and their ability to modulate mitochondrial function in primary neonatal rat ventricular myocytes (NRVMs). <b>Results:</b> SHEVs (mean size: 148.9 ± 25.9 nm) and IHEVs (102.9 ± 31.0 nm) exhibited distinct proteomic signatures. SHEV and IHEV contained mostly structural proteins, but also contained 8% and 4% mitochondrial and glycolytic proteins, respectively. Lipidomic analysis revealed higher sphingomyelin and lower cardiolipin in EVs compared to whole tissue. SHEV treatment significantly increased mitochondrial ATP production, basal, and maximal respiration in NRVMs (<i>P</i> < 0.05). Conversely, IHEVs decreased maximal respiration without altering ATP production. Neither EV type exhibited intrinsic mitochondrial activity. <b>Conclusion:</b> Regionally distinct EVs within the human heart have the capacity to modulate mitochondrial function. These findings suggest that cardiac EVs may act as localized regulators of cardiomyocyte bioenergetics.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1582-1599"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benedikt Kirchner, Christian Grätz, Johannes Kersting, Martina Schuster, Marlene Reithmair, Markus List, Michael W Pfaffl
{"title":"Comprehensive and bias-aware analysis of small RNA NGS data for biomarker detection with caRNAge.","authors":"Benedikt Kirchner, Christian Grätz, Johannes Kersting, Martina Schuster, Marlene Reithmair, Markus List, Michael W Pfaffl","doi":"10.20517/evcna.2026.78","DOIUrl":"https://doi.org/10.20517/evcna.2026.78","url":null,"abstract":"<p><p><b>Aim:</b> Small RNA sequencing (small RNA-Seq) is a widely used and important method for biomarker discovery in extracellular vesicles (EVs), which carry small RNAs among their cargo and protect them from degradation in liquid biopsies. However, existing computational tools for small RNA-Seq data are not tailored to EV-RNA. <b>Methods:</b> We present comprehensive and bias-aware analysis of small RNA gene expression (caRNAge), a biomarker discovery pipeline for small RNA-Seq data intended for users without extensive bioinformatic expertise. Ready to use as a Snakemake pipeline, caRNAge assists users in bias-aware normalization, differential gene expression analysis, and pathway over-representation analysis. <b>Results:</b> Possible confounding factors can be identified and corrected to maximize data comparability between experiments and biomarker robustness. caRNAge is not limited to miRNAs; it also supports the detection of miRNA isomer (isomiRs), tRNA-derived fragments (tRFs), transfer RNA (tRNAs), and other small RNA species, thereby enhancing the specificity of biomarker signatures. Specific tissues can be selected for target prediction and pathway analysis to eliminate false-positive results. All results are provided in accessible and interactive HTML reports. We provide example data for each step of the pipeline to demonstrate caRNAge's capabilities and advantages across three EV-miRNA biomarker discovery use cases. The pipeline is not limited to EV-miRNA data but can be used for data evaluation in any small RNA-Seq experiment. <b>Conclusion:</b> By assisting users at every step of the discovery workflow, caRNAge fills an important gap in the field of EV-associated transcriptomic biomarker development. The pipeline is freely available at https://gitlab.lrz.de/kirchner/carnage.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1554-1581"},"PeriodicalIF":8.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Engineering <i>Tripterygium wilfordii</i>-derived exosome-like nanoparticles for targeted therapy in rheumatoid arthritis.","authors":"Yunyi Yang, Zhi Gong, Gongming Shi, Yong Yang, Yun He, Hongjie Yang, Dajian Yang, Xiaohong Yang","doi":"10.20517/evcna.2026.66","DOIUrl":"10.20517/evcna.2026.66","url":null,"abstract":"<p><p><b>Aim:</b> Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by excessive activation of pro-inflammatory macrophages and elevated levels of reactive oxygen species (ROS), resulting in synovial hyperplasia, cartilage destruction, and joint dysfunction. This study aimed to develop an engineered <i>Tripterygium wilfordii</i>-derived exosome-like nanoparticle system (TWELP@GlcN-HA) that integrates antioxidant, anti-inflammatory, immunomodulatory, and joint-targeting activities for synergistic RA therapy. <b>Methods:</b> <i>Tripterygium wilfordii</i>-derived exosome-like nanoparticles (TWELP) were isolated from fresh <i>Tripterygium wilfordii</i> and sequentially surface-modified with glucosamine (GlcN) for cartilage protection and hyaluronic acid (HA) for targeted uptake by inflammatory cells. Their physicochemical properties, including morphology, particle size, structural integrity, and surface potential, were systematically characterized. <i>In vitro</i> assays were performed to evaluate ROS scavenging, inhibition of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)], and macrophage polarization. Biodistribution and therapeutic efficacy were evaluated in a collagen-induced arthritis (CIA) mouse model by assessing synovial inflammation, cartilage damage, joint morphology, and joint function. <b>Results:</b> TWELP@GlcN-HA exhibited a uniform spherical morphology, stable surface potential, and preserved structural integrity. <i>In vitro</i>, it efficiently scavenged ROS, suppressed TNF-α and IL-6 secretion, and promoted macrophage polarization from M1 to M2, thereby restoring immune homeostasis. <i>In vivo</i>, HA-mediated targeting promoted nanoparticle accumulation in inflamed joints. TWELP@GlcN-HA significantly alleviated synovial inflammation and cartilage destruction, improved joint morphology and function, and exhibited excellent biosafety with no systemic toxicity. <b>Conclusion:</b> TWELP@GlcN-HA provides a multifunctional combinatorial strategy for RA treatment by synergistically regulating ROS, reprogramming pro-inflammatory macrophages, protecting cartilage, and achieving targeted joint delivery. Its enhanced therapeutic efficacy and favorable safety profile make it a promising candidate for future clinical translation in RA management.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1534-1553"},"PeriodicalIF":8.5,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nucleic acids in medicinal plants and their pharmaceutical potential.","authors":"Xiaoyan Qin, Fangwen Jiao, Hongzhi Qiao","doi":"10.20517/evcna.2026.57","DOIUrl":"10.20517/evcna.2026.57","url":null,"abstract":"<p><p>Medicinal plants, as a core constituent of traditional medicine, provide an essential foundation for preventing and treating human diseases. Research on their pharmacologically active constituents has long focused on secondary metabolites, including alkaloids, terpenoids, flavonoids, and other compounds. However, with the rapid advancement of molecular biology techniques, nucleic acids have gradually become a research focus as a novel class of active components in medicinal plants that possess both nutritional and regulatory functions. This paper systematically reviews the types, characteristics, extraction techniques, pharmacological actions, and mechanisms of nucleic acids (including coding and non-coding RNAs) in medicinal plants. It also discusses current challenges and future directions for medicinal plant-derived nucleic acids in new drug development, providing a theoretical reference and technical basis for in-depth research and industrial application in this field.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1517-1533"},"PeriodicalIF":8.5,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Migrasomes in cancers: from the biogenesis mechanism to therapeutic implications.","authors":"Luomeng Qian, Shoujun Wang, Paulina Kucharzewska, Jiachang Li, Sihe Zhang","doi":"10.20517/evcna.2026.70","DOIUrl":"10.20517/evcna.2026.70","url":null,"abstract":"<p><p>Migrasomes are a newly identified class of extracellular vesicles (EVs) with a distinctive pomegranate-like morphology that are generated specifically from migrating cells. They are increasingly recognized as critically important mediators of intercellular communication involved in diverse physiological and pathological processes. However, their roles in cancers remain incompletely defined, and a consensus on migrasome-mediated malignant phenotypes is still lacking. In this review, we first summarize the current knowledge of migrasome biogenesis, distribution, and isolation methodologies. We then systematically discuss the multifaceted roles of migrasomes within the tumor microenvironment (TME), with particular emphasis on their contribution to cancer metastasis, progression and drug resistance. Furthermore, we explore the potential clinical applications of migrasomes in cancer diagnosis and therapy, and outline the key challenges and controversies that hinder their translation into clinical practice. Overall, this review provides an updated perspective on the roles of migrasomes in cancer biology and highlights the emerging opportunities for migrasome-informed targeted therapeutics.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1472-1495"},"PeriodicalIF":8.5,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Aptamer-based technologies for extracellular vesicle analysis and engineering: from isolation to functional applications.","authors":"Xuefei Li, Youyu Zhang, Danping Zhang, Theerakamol Pengsakul, Ying Qiao, Jiang Zheng, Lixing Huang","doi":"10.20517/evcna.2026.106","DOIUrl":"10.20517/evcna.2026.106","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are natural mediators of intercellular communication and hold promise for disease diagnosis and drug delivery, yet their intrinsic heterogeneity complicates isolation, molecular profiling, and targeted delivery. Aptamers, owing to their high affinity, specificity, chemical tunability, and scalable synthesis, offer a flexible molecular toolkit to address these challenges. In this review, we highlight recent progress in integrating aptamers into EV research across three interconnected domains: (1) the selection of aptamers against EV-associated surface markers; (2) the development of aptamer-based methods for EV capture and isolation; (3) the use of aptamer-functionalized EVs for targeted drug delivery and immunomodulation. We also discuss outstanding challenges, particularly the need for selection strategies that better preserve native EV epitope conformations and the rational design of multifunctional aptamer architectures. Looking forward, the convergence of aptamer technology with EV biology is expected to enable aptamer-drug conjugates and minimally invasive, dynamic liquid biopsy approaches for major diseases such as cancer, ultimately advancing early diagnosis and precision medicine.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1496-1516"},"PeriodicalIF":8.5,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qiru Guo, Yaling Chen, Gongfu Ji, Chang Shu, Yueping Qiu, Luo Fang
{"title":"Cytoskeleton governs exosome-mediated drug resistance under mechanical stress.","authors":"Qiru Guo, Yaling Chen, Gongfu Ji, Chang Shu, Yueping Qiu, Luo Fang","doi":"10.20517/evcna.2026.08","DOIUrl":"10.20517/evcna.2026.08","url":null,"abstract":"<p><p>Drug resistance remains a critical obstacle in solid tumor therapy. While most studies have focused on chemical signaling within the tumor microenvironment, accumulating evidence has revealed that mechanical stress is a pivotal but underappreciated driver of drug resistance. Unlike previous reviews that have separately addressed mechanotransduction, exosome biology, and autophagy, this review proposes a vertically integrated framework - the \"mechanical stress-cytoskeleton-exosomes-autophagy\" axis - that connects these domains into a causal cascade from mechanical stress sensing to the dissemination of population-level resistance. Our central hypothesis is that cytoskeletal remodeling, driven by shear stress, matrix stiffness, and compressive stress, not only transduces mechanical signals intracellularly but also encodes these physical cues into exosomal cargo. These exosomes, in turn, transmit stress memory to recipient cells and trigger protective autophagy, thereby propagating drug-resistant phenotypes across heterogeneous tumor regions. We synthesize current evidence across biomechanics, vesicle trafficking, and stress biology and critically evaluate the intervention strategies that target each node of this axis. By reframing drug resistance as a mechanically propagated, exosome-mediated process, this review provides a new conceptual foundation and actionable directions for overcoming treatment failure.</p>","PeriodicalId":520322,"journal":{"name":"Extracellular vesicles and circulating nucleic acids","volume":"7 3","pages":"1445-1471"},"PeriodicalIF":8.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}