Permeable nanoreactor eye drop for enzymatic cascade-mediated treatment for acute retinal injury model mimicking geographic atrophy

Geographic atrophy (GA), the most prevalent form of age-related macular degeneration (AMD), remains clinically challenging due to its complex pathogenesis. Using an acute retinal injury model that mimics GA pathology (oxidative stress-induced retinal apoptosis), we identify enzymatic cascade restoration as a promising therapeutic strategy. To overcome ocular delivery barriers, we engineer zwitterionic nanocages for co-delivering catalase (CAT) and superoxide dismutase (SOD) (Z(CAT&SOD)). These optimized nanocages achieve a remarkable 9.32% ocular penetration rate, which significantly outperforms free peroxidase (0.54%), through conjunctival-sclera-retina and conjunctival-blood-retina penetration pathways, and achieve therapeutic efficacy comparable to intravitreal injection. In the chronic management of GA, the non-invasive Z(CAT&SOD) eye drops show superior therapeutic effects to the current gold standard clinical antioxidants and lutein supplement. Therefore, this work reveals the possible association between retinal peroxidase deficiency and GA progression, and proposes a non-invasive, highly effective zwitterionic nanocage for AMD treatment.