Cornea-Penetrating Nanodrug Co-Delivering VEGF-Silencing siRNA and Lutein for Treating Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, driven by oxidative stress, chronic inflammation, and pathological choroidal neovascularization (CNV). Although intravitreal anti-vascular endothelial growth factor (VEGF) therapies remain the current clinical standard, their invasive nature and requirement for long-term repeated injections present substantial risks and patient burden, underscoring an urgent need for noninvasive therapeutic alternatives. Here, we develop a noninvasive, cornea-penetrating nanodrug based on chitosan-modified lipid-polymer hybrid nanoparticles (LPNPs) for co-delivery of lutein and VEGF-silencing siRNA (Chi@Lu/si NPs) to treat AMD. The structurally stabilized nanoparticles overcome the intrinsic instability of siRNA and the poor solubility of lutein, while the chitosan coating confers strong mucoadhesion and transient modulation of epithelial tight junctions, enabling a 3.3-fold enhancement in trans-epithelial transport across the ocular surface. Once delivered to the posterior segment, lutein effectively scavenges excessive reactive oxygen species and suppresses inflammatory cascades, whereas siRNA-VEGF achieves precise VEGF gene silencing, collectively interrupting the pathological cycle driving CNV progression. In a laser-induced CNV mouse model, topical administration of Chi@Lu/si NPs twice daily exerted potent inhibitory effects on neovascularization, with therapeutic efficacy comparable to that of intravitreal bevacizumab, reducing CNV lesion thickness to 58.9% of pre-treatment levels while maintaining excellent ocular biocompatibility.