Engineered Exosome-Based Senolytic Therapy Alleviates Stroke by Targeting p21CD86 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, p21CD86 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 , , , and . To specifically target and eliminate these pathogenic p21CD86 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 p21CD86 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 p21CD86 microglia as a novel therapeutic strategy, highlighting the potential of exosome-based senolytic anti-inflammatory therapy for stroke and other central nervous system disorders.