Neuroprotective effects of Berberine-loaded BMSCs-apoptotic extracellular vesicles on retinal ganglion cells: therapeutic potential for glaucomatous injury.

Glaucoma is a leading cause of irreversible blindness, primarily driven by the progressive degeneration of retinal ganglion cells (RGCs). In this study, we report the novel application of bone marrow mesenchymal stem cells (BMSCs)-derived apoptotic extracellular vesicles (ApoEVs) in a glaucomatous ischemia/reperfusion (IR) model. ApoEVs exhibited remarkable anti-inflammatory properties, were efficiently internalized by retinal neurons, promoted RGC survival, and preserved visual function. Transcriptomic analysis revealed that ApoEV treatment significantly downregulated Irgm1, an inflammation-related gene. Notably, this study also established a new drug delivery strategy by successfully loading Berberine (Ber)-a natural compound with well-documented anti-inflammatory and neuroprotective effects-onto ApoEVs. The combination further enhanced their protective effects on RGCs, with synergistic suppression of inflammation and improved neuronal viability. Mechanistically, this enhancement was mediated through the coordinated inhibition of the MAPK signaling pathway via Irgm1, which is identified here for the first time as a potential therapeutic target in glaucoma. Collectively, our findings highlight the dual function of Berberine-loaded ApoEVs as a potent cell-free therapeutic strategy that integrates targeted anti-inflammatory and neuroprotective effects, offering a promising new avenue for the treatment of glaucomatous neurodegeneration.