Targeted delivery of miR-199a-5p by RGD-modified HUMSC- extracellular vesicles regulates ocular neovascularization via suppression of endothelial–mesenchymal transition

• Constructed an engineered extracellular vesicle RGD-EV@miR-199a-5p for alleviating ocular neovascularization and vascular leakage, exhibiting good targeting ability and enhanced anti-neovascularization efficacy. • The engineered RGD-EV@miR-199a-5p demonstrated a robust synergistic effect in suppressing endothelial–mesenchymal transition(EndMT) progression. • Mechanistically, RGD-EV@miR-199a-5p enabled highly efficient enrichment and sustained release of miR-199a-5p, downregulating genes associated with EndMT by targeting SNAI1 and modulating the Wnt/β-catenin pathway. • Provided an innovative strategy for treating ocular neovascularization and offered new insights into achieving precision, effectiveness, and safety in ophthalmic therapy. Ocular neovascular diseases can severely impair vision and increase patients’ economic burden and psychological stress. Currently, anti-VEGF therapy fails to benefit all patients, thus calls for new therapeutic targets and efficient delivery approaches. In this study, we constructed engineered extracellular vesicle—RGD-EV@miR-199a-5p—which are modified with RGD peptide and loaded with miR-199a-5p. This engineered extracellular vesicle offers a dual advantage: the RGD peptide enables precise targeting to neovascular niches, while the combination of miR-199a-5p and the EV platform synergistically inhibits angiogenesis. Experiments in both cultured cells and animals revealed that RGD-EV@miR-199a-5p significantly colocalized with neovascular endothelial cells. Mechanistically, it directly binds to the downstream target gene SNAI1, thereby suppressing protein translation and Wnt/β-catenin signaling. This modulation of the endothelial-mesenchymal transition process ultimately inhibits neovascularization and vascular leakage. Moreover, no significant toxicity was detected at either the cellular or animal level. Collectively, our findings suggest that RGD-EV@miR-199a-5p may represent a promising approach for precisely treating ocular neovascular diseases.