Nanomaterial-enabled delivery of plant-derived bioactive metabolites for diabetic retinopathy: from evidence appraisal to preclinical translation

As a leading cause of preventable blindness globally, diabetic retinopathy (DR) requires innovative treatments beyond conventional anti-VEGF therapies, which face limitations in efficacy, administration burden, and multifactorial targeting. Plant-derived bioactive metabolites (e.g., quercetin, puerarin) have been reported to modulate multiple DR-relevant pathways in preclinical studies against DR pathogenesis, including modulation of angiogenesis, oxidative stress, and inflammation. However, their clinical translation is hindered by compound- and route-dependent pharmacokinetic challenges, including poor solubility, extensive metabolism, rapid ocular clearance, and restricted posterior-segment exposure. This review explores nanomaterial-enabled delivery systems to overcome these barriers, detailing platforms such as polymeric nanoparticles, lipid-based carriers, and exosomes engineered to enhance solubility, penetration, and sustained release. Key strategies including barrier-specific size optimization, surface engineering, and ligand functionalization are critically analyzed. Integrated preclinical frameworks utilizing in vitro models and in vivo rodent studies, along with pharmacokinetic and safety evaluations, are emphasized. Finally, regulatory considerations and clinical trial challenges are addressed. Nanomaterial-mediated delivery represents a paradigm shift and may provide a promising translational strategy for plant-derived bioactive metabolites in DR, but its clinical relevance will depend on rigorous ocular pharmacokinetic, efficacy, safety, manufacturing, and regulatory validation.