Engineered MEVs for photoreceptor-targeted delivery of USP25 to alleviate diabetic retinopathy

Diabetic retinopathy (DR) is the major cause of vision decline in adults worldwide. Photoreceptor loss is considered a main pathogenesis of retinal dysfunction in DR. Recently, mesenchymal stem cell-derived extracellular vesicles (MEVs) treatment has been considered a promising cell-free approach for retinal disorders. However, the role and mechanism of MEVs in alleviating photoreceptor injury in DR remain unclear. In this study, MEV treatment improved retinal function and inhibited photoreceptor apoptosis in db/db mice. Mechanistically, the deubiquitinating enzyme ubiquitin-specific peptidase 25 (USP25) in MEVs was responsible for the MEV-mediated photoreceptor therapy by inhibiting hyperglycemia-induced αA-crystallin (CRYAA) ubiquitination. Moreover, USP25-enriched MEVs modified with the photoreceptor-targeting peptide MH42 (MEVs^MH42-USP25) were prepared by genetic engineering and surface conjugation. MEVs^MH42-USP25 exhibited elevated repairing efficiency to attenuate retinal dysfunction and photoreceptor loss in db/db mice. Our study develops an MEV-based nanocarrier for photoreceptor-targeted delivery and highlights the effectiveness of MEVs^MH42-USP25 as novel therapeutics for DR.