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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:Ischemic stroke is a major cause of death and disability, in which neuroinflammation exacerbates injury. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) offer therapeutic potential but face translational hurdles in scalable production, rapid systemic clearance, and inefficient targeted delivery.Methods:We engineered an implantable alginate-microsphere system encapsulating EV-secreting MSCs and displaying the RGD-4C peptide (ACDCRGDCFC) on its surface. This platform functions as a bioreactor that sustains the release of functionalized EVs with enhanced targeting to the ischemic brain. Proteomics analyses compared EVs derived from 3D-microsphere cultures and conventional 2D cultures. Efficacy was evaluated in a mouse stroke model with intraperitoneal microsphere implantation, assessing biodistribution, neuroinflammation, microglial polarization, and recovery.Results:The system sustained the release of targeted EVs, demonstrating proteomic enrichment of anti-inflammatory cargo. In vivo, the platform enhanced EV accumulation in the ischemic brain, reduced neuroinflammation, shifted microglia toward a reparative phenotype, and significantly improved neuronal survival and functional recovery.Conclusion:This integrated platform represents a promising preclinical strategy for treating ischemic stroke and has potential applications in other neuroinflammatory diseases. This system circumvents the need for EV extraction and storage while eliminating the peak-and-trough kinetics of bolus injections, and suggests potential for future translation pending further validation.<\/jats:p>","DOI":"10.31083\/fbl52994","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:17:49Z","timestamp":1785413869000},"source":"Crossref","is-referenced-by-count":0,"title":["Implantable Microsphere-Mediated Targeted Delivery of Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuates Neuroinflammation and Promotes Recovery After Cerebral Ischemia"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3853-8734","authenticated-orcid":true,"given":"Yiran","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, 211166 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4933-0393","authenticated-orcid":true,"given":"Xiaorui","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, 211166 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2683-3222","authenticated-orcid":true,"given":"Xiao","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, 211166 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5173-6117","authenticated-orcid":true,"given":"Yiwen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, 211166 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2675-8197","authenticated-orcid":true,"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7879-1445","authenticated-orcid":true,"given":"Tian","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, 211166 Nanjing, Jiangsu, China"},{"name":"Wuxi Medical Center, The Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Iadecola C, Buckwalter MS, Anrather J. 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