Extracellular vesicles conjugated with c(RGDyk) peptide targeting integrin αVβ3 repair optic nerve injury through YAP/TAZ and Smad2/3 signaling.

Extracellular vesicles (EVs) derived from mesenchymal stem cells have therapeutic potential for optic nerve injury. However, further investigations are needed to increase their efficacy. In this study, we tried to enhance targeting and recovery function of EVs using conjugation with integrin αVβ3 antagonist-c(RGDyk) peptide. The molecular mechanism of neuronal repair was investigated as a potential treatment for optic nerve injury. EVs were shown to restore effectively the abnormal regulations of neuronal markers in optic nerve injury models. Notably, the functionally optimized c(RGDyK)_EVs exhibited superior targeting capabilities and modulated neuroregeneration in cases of hypoxic damage and inflammation. Single-cell RNA-seq analysis of R28 cells revealed significant regulation of transcription of genes involved in retinal ganglion cell (RGC) regeneration, neuronal growth, and inflammation by c(RGDyK)_EVs via the Yap-Taz signaling pathway. This study highlighted the enhanced therapeutic potential of c(RGDyK)_EVs over naïve EVs in the context of optic nerve disease. The findings suggested that c(RGDyK)_EVs hold promise as an alternative therapy for optic nerve injury.