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.