Apoferritin-conjugated melanin nanoparticles rescue photoreceptor degeneration via dual iron chelation and ROS scavenging in dry AMD therapy

Oxidative stress in the retina and dysregulation of iron homeostasis are established as central pathogenic mechanisms in dry age-related macular degeneration (dAMD). Nonetheless, effective clinical treatments to counteract retinal degeneration in this condition are still absent. Our research began with developing a single-cell transcriptome profile of retinal tissue subjected to sodium iodate (NaIO 3 )-induced oxidative injury. This analysis identified ferroptosis in photoreceptor cells as a key driver of disease advancement. Apoferritin (AFn) is a hollow, spherical protein nanocage formed by 24 self-assembled subunits, enabling supramolecular iron storage through ferroxidase-mediated mineralization while providing dynamic iron buffering and antioxidant protection in biological systems. We then engineered a biomimetic nanoparticle, AFn-MNP, by combining Afn with melanin nanoparticles (MNP). AFn-MNP displayed significant ferrous ion-chelating ability and antioxidant activity, effectively mitigating NaIO 3 -triggered photoreceptor ferroptosis in vitro and in vivo. Significantly, a single intravitreal injection of 10 μg AFn-MNP effectively counteracted visual impairment in NaIO 3 -induced dAMD model mice, reversed damage to photoreceptor synaptic terminals, and significantly alleviated photoreceptor degeneration and retinal oxidative injury.In summary, our results indicate that AFn-MNP holds significant promise as a novel therapy for dAMD and other retinal degenerative diseases linked to oxidative damage and impaired iron metabolism.