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In this study, we uncovered a critically important yet previously unexamined cell population, p21<jats:sup>+<\/jats:sup>CD86<jats:sup>+<\/jats:sup> microglia, which accumulated in ischemic region. Unexpectedly, we discovered that p21 interacted with C\/EBP\u03b2, driving C\/EBP\u03b2\u2010dependent transcription and upregulating key pro\u2010inflammatory factors such as <jats:italic>Il6<\/jats:italic>, <jats:italic>Il1\u03b2<\/jats:italic>, <jats:italic>Cxcl2<\/jats:italic>, and <jats:italic>Cxcl10<\/jats:italic>. To specifically target and eliminate these pathogenic p21<jats:sup>+<\/jats:sup>CD86<jats:sup>+<\/jats:sup> microglia, we engineered exosomes with a peptide that selectively binds CD86<jats:sup>+<\/jats:sup> microglia and loaded them with the senolytic Quercetin. Furthermore, we developed an optimized, stable Que@micro\u2010Exo therapeutic formulation. Systemic administration of Que@micro\u2010Exo robustly reduced p21<jats:sup>+<\/jats:sup>CD86<jats:sup>+<\/jats:sup> microglia and suppressed their pro\u2010inflammatory phenotype. Notably, functional analyses revealed that Que@micro\u2010Exo treatment mitigated blood\u2010brain barrier disruption, promoted beneficial microglial polarization, decreased neutrophil infiltration, and significantly enhanced functional recovery following cerebral ischemia, all with a favorable safety profile. Our preclinical findings lay the foundation for targeting p21<jats:sup>+<\/jats:sup>CD86<jats:sup>+<\/jats:sup> microglia as a novel therapeutic strategy, highlighting the potential of exosome\u2010based senolytic anti\u2010inflammatory therapy for stroke and other central nervous system disorders.<\/jats:p>","DOI":"10.1002\/exp.20240349","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T17:19:51Z","timestamp":1741713591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Engineered Exosome\u2010Based Senolytic Therapy Alleviates Stroke by Targeting p21<sup>+<\/sup>CD86<sup>+<\/sup> Microglia"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6198-2085","authenticated-orcid":false,"given":"Jialei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology, China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipo","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Advanced Biotechnology Beijing Institute of Biotechnology  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology, China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001209"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.122.036946"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001"},{"key":"e_1_2_9_5_1","article-title":"Cellular Senescence in Brain Aging and Neurodegeneration","volume":"84","author":"Melo Dos Santos L. 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