Nanoprotection Against Retinal Pigment Epithelium Degeneration via Ferroptosis Inhibition

Abstract Lethal oxidative stress and ferrous ion accumulation‐mediated degeneration/death in retinal pigment epithelium (RPE) exert an indispensable impact on retinal degenerative diseases with irreversible visual impairment, especially in age‐related macular degeneration (AMD), but corresponding pathogenesis‐oriented medical intervention remains controversial. In this study, the potent iron‐binding nanoscale Prussian blue analogue KCa[Fe III (CN) 6 ] (CaPB) with high biocompatibility is designed to inhibit RPE death and subsequently photoreceptor cell degeneration. In mice, CaPB effectively prevents RPE degeneration and ultimately fulfills superior therapeutic outcomes upon a single intravitreal injection: significant rescue of retinal structures and visual function. Through high‐throughput RNA sequencing and sophisticated biochemistry evaluations, the findings initially unveil that CaPB nanoparticles protect against RPE degradation by inhibiting ferroptotic cell fate. Together with the facile, large‐scale preparations and in vivo biosafety, it is believed that the synthesized CaPB therapeutic nanoparticles are promising for future clinical treatment of diverse retinal diseases involving pathological iron‐dependent ferroptosis, including AMD.