Abstract
The breakdown of the blood-retinal barrier (BRB), which induces vascular leakage, represents a critical pathological hallmark underlying severe vision loss in uveitis. The inflammatory response triggers phenotypic alterations in microglia, driving excessive reactive oxygen species (ROS) production and initiating a pro-inflammatory cytokine storm involving multiple inflammatory mediators. This synergistic interaction establishes a self-amplifying pathological cascade that ultimately leads to BRB dysfunction. As a natural bioactive compound, epigallocatechin gallate (EGCG) demonstrates well-established ROS scavenging capacity, while metformin (MET), a clinically approved antidiabetic agent, effectively inhibits inflammatory responses. We used a self-assembly strategy to construct multifunctional nanoparticles (EM NPs) by combining EGCG and MET for the synergistic treatment of uveitis. In the inflammatory microenvironment, EM NPs promoted microglial polarization from M1 to M2 phenotype by suppressing the NF-κB signaling pathway and significantly reduced pro-inflammatory cytokine secretion. In addition, EM NPs suppressed apoptosis in retinal pigment epithelial (RPE) cells, a key constituent of the BRB, and preserved the integrity of tight junction proteins by scavenging ROS and inhibiting the mitochondrial apoptotic pathway, thereby exerting synergistic protective effects on the BRB. In experimental autoimmune uveitis (EAU) rat models, EM NP treatment markedly improved retinal and choroidal perfusion. Our findings demonstrate that EM NPs provide a novel therapeutic approach for uveitis management.