We identified a harmful immune cell type, p21+CD86+ microglia, driving post-stroke inflammation and developed a targeted exosome-based therapy (Que@micro-Exo) to eliminate these cells. This innovative treatment reduced inflammation, alleviated brain damage, and improved recovery in stroke models, offering a promising strategy for stroke and other central nervous system disorders.
Abstract:
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 Il6, Il1β, Cxcl2, and Cxcl10. 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.
Author list:
Jialei Yang*, Shipo Wu, Miao He
How to cite:
J. Yang, S. Wu, M. He, Exploration 2025, 20240349.
https://doi.org/10.1002/EXP.20240349