Iron Homeostasis Restoration via Triple-Pool-Targeted Nanotherapy for Enhanced Amelioration of Age-Related Macular Degeneration

Oxidative stress-induced retinal pigment epithelium (RPE) damage and ferroptosis are critical in retinal degenerative diseases, particularly in age-related macular degeneration (AMD)─a major cause of irreversible blindness. Current clinical AMD treatment is predominantly dependent on intravitreal anti-VEGF administration targeting only late-stage choroidal neovascularization (CNV), with limitations of incomplete response and adverse effects. Herein, a facile synthesis of Nuci@PAM-BR, which was designed by modification of antioxidant bilirubin to the surface and encapsulation of antiferroptosis nuciferine in the hydrophobic cavity of polyamidoamine dendrimers, was reported, thus achieving iron homeostasis restoration via triple-pool-targeted scavenging properties for eradicating CNV in AMD management. Our results demonstrated that Nuci@PAM-BR could significantly attenuate CNV by targeting the detrimental "triple pool" in damaged RPE cells, exhibiting excellent antioxidant and anti-inflammatory properties that contributed to its excellent antiangiogenic effect, achieving an over 80% reduction in leakage area and an over 85% decline in neovascular lesion. Such triple-pool-targeted nanotherapy offers a promising alternative and holds significant potential for the future clinical treatment of diverse fundus neovascularization diseases, including AMD.