Cerium-polyphenol network protects against AMD-associated RPE degeneration via blood-retinal barrier immunomodulation

Age-related macular degeneration (AMD) remains difficult to treat due to the complex pathogenesis of retinal microenvironment (RME). In this study, we developed a cerium-rhein network encapsulated with polyvinylpyrrolidone (CRP NPs) to enhance biocompatibility. CRP NPs exhibited robust catalase (CAT)- and superoxide dismutase (SOD)-like activities and modulated the immune microenvironment within blood-retinal barrier (BRB). In vitro, CRP NPs protected ARPE-19 cells from NaIO 3 -induced damage and preserved BRB integrity by upregulating tight junction proteins and transepithelial electrical resistance (TEER). Mechanistic studies using RNA-seq, western blotting, and molecular docking revealed that rhein released from NPs inhibits the receptor for advanced glycation end products (RAGE) signaling pathway. Together with the reactive oxygen species (ROS)-scavenging activity of cerium (Ce 3+ / 4+ ), this effect contributed to the suppression of ferroptotic cell death and attenuates the “HMGB1-RAGE-ROS-ferroptosis-HMGB1” vicious cycle. Besides, CRP NPs shifted microglia from a pro-inflammatory activation to an anti-inflammatory phenotype by reducing the release of high mobility group box-1 protein (HMGB1) and calreticulin (CALR). This immunomodulation led to remodeling of the RME, as evidenced by reduced levels of IL-1β, IL-6, TNF-α, and COX2. In a NaIO 3 -induced dry AMD-like degeneration mouse model, treatment with CRP NPs significantly preserved RPE, improved visual function, and restored BRB integrity. Collectively, these findings demonstrate that CRP NPs present a multimodal therapeutic platform for AMD-like retinal degeneration, acting through immunomodulation of the RME and inhibition of ferroptosis in retinal pigment epithelium.