Small extracellular vesicle-encapsulated miR-146a suppresses neuroretinal pyroptosis through inhibition microglial activation in retinal vein occlusion

Retinal vein occlusion (RVO) is the second most prevalent retinal vascular disease worldwide and represents a major contributor to visual impairment. However, its pathogenesis is complex, and recurrence after treatment is common. Small extracellular vesicles (sEVs) and their cargoes have demonstrated great potential in disease diagnosis and treatment. This study investigated the expression profile of microRNA (miRNA), a major sEV cargo, in the circulating plasma of patients with RVO. The results revealed that the miR-146a level in plasma-derived sEVs is closely associated with the onset and prognosis of RVO. Using a mouse RVO model, we demonstrated that miR-146a overexpression effectively alleviated retinal edema by suppressing microglial activation and inhibiting neuroretinal pyroptosis. In vitro studies further revealed that miR-146a prevents microglial activation, reduces proinflammatory cytokine levels, and inhibits neuronal cell death. Transcriptomic analysis of miR-146a-treated retinas from RVO mice revealed that the primary biological processes and signaling pathways involved are related to inflammatory responses. We further identified Traf6 and Nucks1 as potential targets of miR-146a in RVO. Additionally, microglia-derived sEVs were used to load miR-146a to construct engineered sEVs (sEVmiR-146a). The results indicated that sEVmiR-146a efficiently delivered miR-146a to the retinal cells, subsequently maintaining retinal homeostasis in RVO models. Furthermore, sEVmiR-146a significantly increased miR-146a levels in microglial cells in vitro, thereby suppressing inflammatory responses and the expression of target genes. In conclusion, extracellular vesicle-encapsulated miR-146a shows promise as a potential diagnostic biomarker and therapeutic strategy for retinal vascular diseases.