Dual-Target ROS-Driven Spatiotemporal Senolysis for Vascular Repair and Immune Microenvironment Reprogramming in the Treatment of Ocular Fundus Neovascularization.

Abstract

Ocular fundus neovascularization (OFN) is a leading cause of irreversible vision loss. Conventional antivascular endothelial growth factor (anti-VEGF) therapies indiscriminately suppress pathological and reparative angiogenesis and fail to correct the senescence- and inflammation-driven microenvironment that sustains disease progression. Senescent endothelial cells (ECs) form the structural scaffold of pathological vessels, while neighboring senescent microglia exacerbate inflammatory signaling, together deteriorating the reactive oxygen species (ROS)-rich vascular-immune microenvironment. Here, we develop an injectable ROS-responsive senolytic hydrogel (PCC1/PHCF-Gel) that enables lesion-activated, sustained intraocular release of procyanidin C1 (PCC1), overcoming rapid clearance, oxidative degradation, and poor lesion retention associated with free PCC1. In oxygen-induced retinopathy and choroidal neovascularization models, PCC1/PHCF-Gel markedly reduces retinal senescence, suppresses pathological neovascularization, and restores neuroretinal function, outperforming symptom-directed therapies anti-VEGF therapy. Single-cell RNA sequencing reveals selective elimination of two pathogenic senescent cell subpopulations-CXCR4ECs and IFITM3microglia-thereby disrupting the reinforcing cycle of vascular and immune senescence and promoting reparative vascular regeneration. These findings establish a multifunctional, spatiotemporally controlled therapeutic paradigm and highlight PCC1/PHCF-Gel as a promising translational strategy for the precision treatment of OFN.