Neuron‐Derived Vesicular circMagi1 Restrains Vascular Repair After Ischemic Stroke by Promoting TRIM65‐Mediated ANXA2 Degradation

Circular RNAs (circRNAs) contribute to stroke pathogenesis, yet their intercellular functions within the ischemic neurovascular unit remain poorly defined. Profiling of plasma extracellular vesicles (EVs) revealed a higher abundance of circMagi1 in patients with acute ischemic stroke compared with healthy controls. This upregulation was recapitulated in the ischemic mouse brain, where cell-type-resolved analyses identified injured neurons as a primary source of circMagi1-containing EVs that accumulate in endothelial cells. Mechanistically, endothelial circMagi1 binds ANXA2 and enhances its engagement with TRIM65, thereby promoting TRIM65-mediated ANXA2 ubiquitination and proteasomal degradation and restraining angiogenesis. To therapeutically target this axis in vivo, treatment with siCircMagi1-RVG-EVs was initiated on post-stroke day 1 and maintained thereafter, while siTrim65-Ang2-EVs were introduced from either day 1 or day 9. Among the schedules tested, adding siTrim65-Ang2-EVs from day 9 was associated with greater neurovascular recovery than sustained circMagi1-targeted treatment alone or co-initiation on day 1. Together, these findings delineate a vesicle-mediated signaling axis linking neuronal injury to impaired vascular repair and support further evaluation of delayed TRIM65 inhibition during sustained circMagi1 suppression.