Natural antioxidant products and nanomaterial-based delivery systems for the amelioration of diabetic retinopathy: mechanisms, applications, and translational perspectives.

Diabetic retinopathy (DR) is a leading global cause of vision loss, closely linked to hyperglycemia-induced oxidative stress, chronic inflammation, and pathological angiogenesis. Natural antioxidants exhibit great therapeutic potential against DR but are severely limited by poor solubility, low bioavailability, and insufficient ocular delivery. This review systematically summarizes the classification, pharmacological mechanisms, and therapeutic values of natural antioxidants in DR, and highlights advances in nanotechnology-based delivery systems to improve efficacy and clinical translation. We integrate preclinical and clinical studies focusing on key pathways including Nrf2/HO-1, NF-κB, NLRP3 inflammasome, and VEGF/HIF-1α. Flavonoids, polyphenols, carotenoids, and alkaloids exert multi-target effects by scavenging ROS, suppressing inflammation, and inhibiting pathological angiogenesis. Nanocarriers including lipid-polymer hybrid nanoparticles, self-nanoemulsifying drug delivery systems (SNEDDS), nanozymes, and lignin-based hydrogels significantly enhance solubility, corneal penetration, retinal targeting, and therapeutic efficacy. Representative nanoformulations effectively alleviate retinal oxidative damage, inflammation, and neovascularization. Natural antioxidants are promising DR candidates, and nanotechnology overcomes translational barriers. This review offers updated insights for developing natural product-based nanomedicines and proposes standardized formulations, biomarker-guided personalized therapy, and multi-target strategies to accelerate clinical translation.