Melanin‐Like Nanomedicine Functions as a Novel RPE Ferroptosis Inhibitor to Ameliorate Retinal Degeneration and Visual Impairment in Dry Age‐Related Macular Degeneration

Abstract Ferrous ion accumulation and lethal oxidative stress mediate irreversible retinal pigment epithelial (RPE) cell ferroptosis and subsequent photoreceptor degeneration, a potential key pathogenic factor in the onset of dry age‐related macular degeneration (dAMD), causing irreversible vision loss in the global elderly population. However, currently, no effective interventional treatment strategy exists in clinical practice. Herein, lesion site‐targeted melanin‐like nanoparticles, named ConA‐MelNPs, are designed as a novel ferroptosis inhibitor for retinal degenerative diseases. ConA‐MelNPs possessed chelating iron ion characteristics, alleviating severe mitochondrial damage caused by oxidative stress and protecting RPE cells from ferroptosis induced by sodium iodate (NaIO 3 ). In a preclinical dAMD mouse model, a single intravitreal injection of ConA‐MelNPs yielded significant responses in electroretinograms and visually‐driven optomotor responses in visually impaired mice, resisting the challenge posed by secondary NaIO 3 ‐induced injuries, with the long‐term sustainability of its therapeutic effect. Mechanistically, ConA‐MelNPs achieve a therapeutic effect by interrupting the detrimental cascade involving “RPE cell ferroptosis, lethal oxidative stress, and microglial proinflammatory activation,” affording the restoration of retinal homeostasis. The synthesized ConA‐MelNPs demonstrated good biosafety, with no detected ophthalmic or systemic side effects. Collectively, ConA‐MelNPs are proposed as a promising therapeutic option for atrophic retinal diseases such as dAMD.