Sca-1+ Bone Marrow Stem Cell-Derived Small Extracellular Vesicles Protect Against Retinal Ischemia-Reperfusion Injury Through Rab7a-Mediated STING Autophagic-Lysosomal Degradation in Microglia

Retinal ischemia-reperfusion (I/R) injury is widely considered a common pathological process underlying various eye diseases, including glaucoma. No effective treatments for retinal I/R injury are currently available. In this study, we isolated Sca-1⁺ (BMC-Sca-1⁺) and Sca-1⁻ (BMC-Sca-1⁻) cell subpopulations from the bone marrow cells of C57BL/6J mice and extracted small extracellular vesicles (sEVs) from each subpopulation. We established a mouse model of retinal I/R injury and found that sEVs derived from BMC-Sca-1⁺ cells significantly improved visual function, maintained retinal structural integrity, and suppressed the apoptosis of retinal ganglion cells (RGCs) in the mouse model. In vitro experiments revealed that sEVs derived from BMC-Sca-1⁺ cells inhibited cGAS–STING–TBK1–IRF3 signaling and decreased the expression of pro-inflammatory cytokines in BV2 microglia subjected to oxygen–glucose deprivation/reoxygenation (OGD/R). Mechanistically, the sEVs restored autophagic flux and facilitated STING–LAMP2 colocalization. Proteomic analysis revealed a significant enrichment of the Rab7a protein in sEVs derived from BMC-Sca-1⁺ cells. Mechanistic experiments indicated that these Rab7a-rich sEVs promoted STING degradation, exerting anti-inflammatory and vision-protective effects. These results suggest that Rab7a plays a key role in this regulatory pathway. This study elucidates the molecular mechanism through which sEVs derived from BMC-Sca-1⁺ cells alleviate glaucomatous retinal I/R injury by promoting autophagy-mediated degradation of STING through Rab7a, thereby providing a new strategy for the preservation of visual function in retinal I/R injury in clinical settings.