Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21⁺CD86⁺ Microglia

Stroke remains the leading cause of neurological mortality and disability worldwide, with post-stroke inflammation significantly hindering neural repair. Despite its critical impact, mechanism-based therapeutic strategies are scarce. In this study, we uncovered a critically important yet previously unexamined cell population, p21⁺CD86⁺ microglia, which accumulated in ischemic region. Unexpectedly, we discovered that p21 interacted with C/EBPβ, driving C/EBPβ-dependent transcription and upregulating key pro-inflammatory factors such as <i>Il6</i>, <i>Il1β</i>, <i>Cxcl2</i>, and <i>Cxcl10</i>. To specifically target and eliminate these pathogenic p21⁺CD86⁺ microglia, we engineered exosomes with a peptide that selectively binds CD86⁺ microglia and loaded them with the senolytic Quercetin. Furthermore, we developed an optimized, stable Que@micro-Exo therapeutic formulation. Systemic administration of Que@micro-Exo robustly reduced p21⁺CD86⁺ microglia and suppressed their pro-inflammatory phenotype. Notably, functional analyses revealed that Que@micro-Exo treatment mitigated blood-brain 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⁺CD86⁺ microglia as a novel therapeutic strategy, highlighting the potential of exosome-based senolytic anti-inflammatory therapy for stroke and other central nervous system disorders.