{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:55:51Z","timestamp":1790898951189,"version":"4.1.0"},"reference-count":145,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Mesenchymal stem\/stromal cell-derived small extracellular vesicles (MSC-sEVs) have emerged as promising cell-free therapeutics for central nervous system (CNS) disorders including stroke, traumatic brain injury (TBI), dementia, and multiple sclerosis (MS). MSC-sEVs offer advantages of low immunogenicity, ease of storage, and ability to cross the blood-brain barrier. This review provides a comprehensive analysis of the mechanisms by which MSC-sEVs have been reported to promote neural repair and recovery in preclinical models, through two convergent categories of action. First, MSC-sEVs exert direct neurorestorative effects, including activation of endogenous neural stem cells via Wnt\/beta-catenin and PI3K\/Akt\/mTOR signaling, neuroprotection through PTEN\/Akt-mediated anti-apoptotic and antioxidant pathways, preservation of mitochondrial function through mitophagy regulation, and promotion of neurite outgrowth and synaptogenesis through cytoskeletal remodeling and growth signaling. Second, MSC-sEVs modulate the injury microenvironment by shifting microglia and infiltrating macrophages toward anti-inflammatory phenotypes through NF-kB pathway modulation, converting reactive astrocytes to neuroprotective states, promoting angiogenesis and blood-brain barrier restoration, and enhancing oligodendrogenesis and remyelination. These effects are mediated largely through the transfer of microRNAs and other bioactive cargo to target cells at the injury site, although the relative contribution of individual cargo components remains to be fully established. We discuss how these actions address the pathophysiology of stroke, Alzheimer's disease, vascular dementia, TBI, and MS, highlighting disease-specific mechanisms and the current gap between preclinical evidence and clinical validation. Finally, we address challenges for clinical translation, including standardization of critical quality attributes and potency assays, route-dependent biodistribution, safety considerations, and dosing optimization. We also discuss engineering strategies for enhanced efficacy, including surface modification for CNS-targeted delivery, source cell preconditioning, cargo engineering, and scaffold-based sustained release systems. Although no clinical trials have yet evaluated MSC-sEV therapy specifically for neurological disorders, the growing body of safety data from non-neurological MSC-sEV trials and the extensive clinical experience with parent MSC therapies provide a foundation for future CNS-focused studies. MSC-sEVs hold substantial potential as a cell-free approach for neurological disorders that currently lack effective regenerative therapies, although realization of this potential will require rigorous clinical validation.<\/jats:p>","DOI":"10.3389\/fncel.2026.1819046","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T04:32:30Z","timestamp":1778214750000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Mesenchymal stromal\/stem cell-derived extracellular vesicles in brain disorders: mechanisms of repair and recovery"],"prefix":"10.3389","volume":"20","author":[{"given":"Masahito","family":"Nakazaki","sequence":"first","affiliation":[{"name":"Department of Neural Regenerative Medicine, School of Medicine, Institute of Regenerative Medicine, Sapporo Medical University","place":["Sapporo, Hokkaido, Japan"]},{"name":"Department of Neurology, Yale University School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Lankford","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine","place":["New Haven, CT, United States"]},{"name":"Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System","place":["West Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Ukai","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, School of Medicine, Institute of Regenerative Medicine, Sapporo Medical University","place":["Sapporo, Hokkaido, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Hirota","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, School of Medicine, Institute of Regenerative Medicine, Sapporo Medical University","place":["Sapporo, Hokkaido, Japan"]},{"name":"Department of Neurology, Yale University School of Medicine","place":["New Haven, CT, United States"]},{"name":"Department of Orthopaedic Surgery, School of Medicine, Sapporo Medical University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Oka","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, School of Medicine, Institute of Regenerative Medicine, Sapporo Medical University","place":["Sapporo, Hokkaido, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, School of Medicine, Institute of Regenerative Medicine, Sapporo Medical University","place":["Sapporo, Hokkaido, Japan"]},{"name":"Department of Neurology, Yale University School of Medicine","place":["New Haven, CT, United States"]},{"name":"Division of Neuroscience, Department of Physiology, Sapporo Medical University School of Medicine","place":["Sapporo, Hokkaido, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Kocsis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale University School of Medicine","place":["New Haven, CT, United States"]},{"name":"Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System","place":["West Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Honmou","sequence":"additional","affiliation":[{"name":"Department of Neural Regenerative Medicine, School of Medicine, Institute of Regenerative Medicine, Sapporo Medical University","place":["Sapporo, Hokkaido, Japan"]},{"name":"Department of Neurology, Yale University School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"282","DOI":"10.3389\/fneur.2019.00282","article-title":"Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms","volume":"10","author":"Alizadeh","year":"2019","journal-title":"Front. 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