Abstract
Background and aim: Age-related macular degeneration (AMD) is a leading cause of vision loss owing to choroidal neovascularization (CNV) and retinal vascular abnormalities. Current anti-VEGF therapies often exhibit limited efficacy in approximately 50% of patients owing to the complex pathological microenvironment, including elevated reactive oxygen species (ROS) levels. This study aimed to develop a multitargeted therapeutic strategy for AMD by leveraging the antioxidant and anti-angiogenic properties of ginsenoside Rg3 (Rg3). Methods: RGD-Rg3@Lips was formulated to encapsulate Rg3 and modified with (Arginine-Glycine-Aspartic Acid, RGD) peptides for targeted delivery. In vitro studies have evaluated the cellular internalization, anti-angiogenic effects, and suppression of oxidative stress and inflammation in ARPE-19 cells. In vivo efficacy was assessed using a laser-induced AMD mouse model, in which an intravitreal injection of RGD-Rg3@Lips was administered. Mechanistic studies have focused on the hypoxia-inducible factor 1-α, (HIF-1α) / vascular endothelial growth factor, (VEGF) signaling pathway and the expression of inflammatory cytokines. Results: RGD-Rg3@Lips demonstrated superior cellular internalization and anti-angiogenic efficacy compared to Rg3@Lips and free Rg3 in vitro, significantly reducing oxidative stress and inflammation. In vivo, RGD-Rg3@Lips markedly reduced CNV formation and vascular leakage in an AMD mouse model. Mechanistically, RGD-Rg3@Lips attenuated oxidative stress, inhibited the HIF-1α/VEGF pathway, and downregulated key inflammatory cytokines including tumor necrosis factor α (TNF-α) and VEGF. RGD modification significantly improved the targeting of CNV lesions, enhancing therapeutic efficacy by specifically binding to vascular surface integrin receptors compared to non-modified liposomes and free Rg3. Conclusion: This study highlights the potential of RGD-Rg3@Lips as a novel multitargeted therapeutic strategy for wet AMD. By combining the antioxidant and antiangiogenic properties of Rg3 with targeted drug delivery, RGD-Rg3@Lips offers a promising approach to address the limitations of current AMD therapies. These findings underscore the value of natural-product-based nanomedicine for the treatment of complex ocular diseases.