Imbalance of immune homeostasis in vascular endothelial cells (VECs) plays a crucial role in blood–brain barrier (BBB) disruption and secondary brain injury following ischemic stroke (IS). Downregulation of CD151 in VECs has demonstrated significant therapeutic effects in IS. However, the role of CD151 in endothelial immune homeostasis remains unclear, and no noninvasive delivery system currently targets CD151 within the ischemic region. Therefore, we aimed to establish an exosome (Exo)-based delivery system capable of targeting and suppressing CD151 in ischemia-injured VECs and to explore the effects and molecular mechanisms of CD151 in regulating VEC immune homeostasis and BBB repair after IS.