Multi-enzyme nanozyme targeting redox-senescence-angiogenesis axis ameliorates pathological angiogenesis in retinopathy models

Abstract

Pathological retinal neovascularization, a hallmark of proliferative diabetic retinopathy and retinopathy of prematurity, is driven by reactive oxygen species (ROS)-induced vascular endothelial cell senescence. Current therapeutic strategies remain limited by their inability to concurrently address the interconnected pathological triad of oxidative stress, inflammation, and cellular senescence. Nanozymes, which mimic the activities of natural enzymes, have emerged as promising candidates for modulating complex disease microenvironments; however, their application in retinal vascular disorders is largely unexplored. Herein, we engineered a polyvinylpyrrolidone (PVP)-stabilized nanozyme, designated PBzyme, that integrates catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD)-like activities within a single nanostructure. Diverging from conventional Fenton-type catalysts, PBzyme scavenges hydrogen peroxide (H₂O₂) through a Fenton-independent mechanism, enabling efficient and sustained ROS elimination without generating harmful hydroxyl radicals. This redox reprogramming capacity effectively alleviated oxidative stress-triggered endothelial cell senescence and suppressed abnormal angiogenesis, primarily through modulation of the MAPK signaling pathway, thereby promoting vascular normalization and restoring retinal microenvironmental stability. In an oxygen-induced retinopathy (OIR) mouse model, PBzyme treatment elicited a pronounced reduction in both the avascular area (approximately 3-fold) and pathological neovascular tufts (approximately 19-fold), as evidenced by retinal whole-mount analyses. Furthermore, in a diabetic retinopathy (DR) mouse model, PBzyme administration significantly mitigated retinal vascular leakage by approximately 3-fold. Collectively, PBzyme represents a novel, biocompatible nanozyme platform that uniquely targets the redox-senescence-angiogenesis axis. Its potent multi-enzyme mimetic activity and distinct non-Fenton mechanism offer a promising and transformative therapeutic strategy for retinal neovascular diseases.