Retinal Microenvironment‐Protected Rhein‐GFFYE Nanofibers Attenuate Retinal Ischemia‐Reperfusion Injury via Inhibiting Oxidative Stress and Regulating Microglial/Macrophage M1/M2 Polarization

Abstract Retinal ischemia is involved in the occurrence and development of various eye diseases, including glaucoma, diabetic retinopathy, and central retinal artery occlusion. To the best of our knowledge, few studies have reported self‐assembling peptide natural products for the suppression of ocular inflammation and oxidative stress. Herein, a self‐assembling peptide GFFYE is designed and synthesized, which can transform the non‐hydrophilicity of rhein into an amphiphilic sustained‐release therapeutic agent, and rhein‐based therapeutic nanofibers (abbreviated as Rh‐GFFYE) are constructed for the treatment of retinal ischemia‐reperfusion (RIR) injury. Rh‐GFFYE significantly ameliorates oxidative stress and inflammation in an in vitro oxygen‐glucose deprivation (OGD) model of retinal ischemia and a rat model of RIR injury. Rh‐GFFYE also significantly enhances retinal electrophysiological recovery and exhibits good biocompatibility. Importantly, Rh‐GFFYE also promotes the transition of M1‐type macrophages to the M2 type, ultimately altering the pro‐inflammatory microenvironment. Further investigation of the treatment mechanism indicates that Rh‐GFFYE activates the PI3K/AKT/mTOR signaling pathway to reduce oxidative stress and inhibits the NF‐κB and STAT3 signaling pathways to affect inflammation and macrophage polarization. In conclusion, the rhein‐loaded nanoplatform alleviates RIR injury by modulating the retinal microenvironment. The findings are expected to promote the clinical application of hydrophobic natural products in RIR injury‐associated eye diseases.