Nanoparticle-Mediated Lutein Delivery for Diabetic Retinopathy: From Blood-Retinal Barrier Crossing to Neurovascular Unit Protection
Abstract
Abstract Diabetic retinopathy (DR) is increasingly understood as an integrated neurovascular unit (NVU) pathology driven by chronic hyperglycemia, rather than solely a microvascular complication. Anti-vascular endothelial growth factor (anti-VEGF) therapy remains limited by repeated intravitreal injections, treatment resistance, and failure to reverse early neurodegeneration. Lutein, a natural carotenoid, may counter these refractory dimensions by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway and suppressing neuroinflammation across NVU components. However, its poor aqueous solubility, chemical instability, and restricted blood–retinal barrier (BRB) permeation limit retinal bioavailability and clinical translation. Nanoscale targeted delivery can improve lutein solubility and stability and enable trans-BRB transport via the enhanced permeability and retention effect or receptor-mediated transcytosis, thereby enhancing precise NVU protection. This review integrates lutein’s mechanisms against DR-related NVU injury, design strategies for nanoscale delivery systems and trans-BRB transport, and preclinical efficacy with translational bottlenecks, to support advancement of lutein from dietary supplement to precision adjuvant therapy for DR. Unlike reviews treating lutein as an isolated nutraceutical or materials target, it connects nanomaterial engineering with clinical translation and regulatory science. Preclinical studies show that nanoformulated lutein improves oral bioavailability, retinal accumulation, and oxidative/inflammatory injury in diabetic models. Translation remains hindered by limited long-term safety data, scalable manufacturing, and unclear regulatory classification. Future priorities include stage-adaptive nanoplatforms, standardized preclinical evaluation, and rigorously designed multicenter clinical trials to establish efficacy, safety, and regulatory readiness.