Quercetin for Diabetic Retinopathy: From Multi-Target Pharmacology to Emerging Retinal Delivery Strategies

Diabetic retinopathy (DR) is a progressive neurovascular complication of diabetes driven by interconnected metabolic stress, oxidative injury, inflammation, vascular dysfunction, regulated cell death, and neurodegeneration. Quercetin, a naturally occurring flavonol, has attracted increasing interest because its pharmacological actions overlap with multiple pathogenic processes involved in DR. Experimental evidence suggests that quercetin may modulate glucose-related metabolic stress, enhance endogenous antioxidant defenses, suppress NF-κB-centered inflammatory signaling and VEGF-associated angiogenesis, regulate apoptosis, autophagy, and ferroptosis, and support neurotrophic signaling. However, these mechanistic advantages have not yet translated into clinical application. Poor aqueous solubility, chemical instability, extensive metabolism, low systemic bioavailability, and limited posterior-segment exposure create a substantial gap between pharmacological activity and therapeutically meaningful retinal concentrations. To address these limitations, lipid nanoparticles, targeted and stimulus-responsive liposomes, hydrogel-based depot systems, nanomicelles, metallic nanostructures and nanozymes, and structurally optimized quercetin derivatives have been investigated to improve drug stability, retinal accumulation, and sustained or responsive release. Importantly, the current evidence remains predominantly preclinical, and findings from non-diabetic ocular models should be distinguished from direct evidence obtained in diabetic retinal models. This review therefore critically integrates the molecular pharmacology of quercetin with its pharmacokinetic limitations and emerging retinal delivery strategies, with particular emphasis on evidence relevance, retinal exposure, treatment durability, safety, and translational feasibility. Future studies should prioritize direct retinal pharmacokinetic assessment, mechanism-linked efficacy in clinically relevant diabetic models, repeated-dose ocular and systemic safety, and comparison or combination with established therapies. Such an evidence-based development framework will be essential to determine whether quercetin-based strategies can progress from multi-target experimental pharmacology to clinically meaningful intervention in DR.