Antioxidant hydrogel eye drops for the effective management of dry age-related macular degeneration by enhancing SIRT1/Nrf2 signaling.

BACKGROUND: Dry age-related macular degeneration (dAMD) is a major cause of irreversible vision loss, in which oxidative stress-induced retinal pigment epithelial injury plays a key role. Astragaloside IV (ASIV) has antioxidant potential but is limited by poor aqueous solubility and ocular bioavailability. PURPOSE: To evaluate the retinal protective effects of an ASIV-loaded antioxidant hydrogel eye drop (ALG) in experimental dAMD. METHODS: A NaIO₃-induced mouse model of dAMD was established. Retinal protection was evaluated using hematoxylin and eosin (H&E) staining, immunofluorescence, ophthalmic imaging, and functional examinations. Cytocompatibility and cellular uptake were assessed in ARPE-19 cells. RESULTS: ALG underwent a sol-gel transition at 35 °C and displayed a markedly sustained release profile compared with free ASIV. In vivo, ALG reduced retinal ROS accumulation and increased retinal sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. In addition, ALG exhibited favorable cytocompatibility. Compared with liposomes and eye drops, the liposome gel also showed greater uptake by ARPE-19 cells. CONCLUSION: ALG attenuated oxidative stress-related retinal injury, and meanwhile retinal SIRT1 and Nrf2 expression increased. Therefore, ALG may exert therapeutic effects against dAMD in association with SIRT1/Nrf2 upregulation.