Retina-targeted siRNA delivery via exosome-liposome hybrid vesicles for AMD treatment

Effective treatment of neovascular age-related macular degeneration (AMD) requires targeted inhibition of vascular endothelial growth factor (VEGF) within the retina. However, delivering therapeutic siRNA to the retinal pigment epithelium (RPE), a key source of pathogenic VEGF, remains a major challenge due to ocular barriers and poor cellular tropism. To address this, we developed a retina-targeted delivery system by engineering exosome-liposome hybrid vesicles that encapsulate VEGF-silencing siRNA (Hybrid-siVEGF). The hybrid design leverages the innate homing capability of RPE-derived exosomes for retinal targeting, combined with the high siRNA loading capacity of synthetic liposomes. In vitro, Hybrid-siVEGF showed significantly enhanced uptake by human RPE cells compared to conventional liposomes, leading to the potent and specific knockdown of VEGF expression and the subsequent inhibition of endothelial cell proliferation. In vivo, a single intravitreal injection of Hybrid-siVEGF in a laser-induced choroidal neovascularization mouse model resulted in efficient accumulation within the retina, significant suppression of pathological angiogenesis, preservation of retinal morphology, and restoration of visual function. Our work establishes exosome-liposome hybrids as an effective and targeted platform for ocular siRNA delivery, offering a promising strategy for RNAi-based therapy for AMD and other retinal disorders.