Glycocalyx-binding and cell-penetrating peptide-modified nanomicelles for enhanced ocular delivery of quercetin and retinal protection in a dAMD model

Dry age-related macular degeneration (dAMD) is a highly prevalent degenerative retinal disease. Quercetin, a bioactive ingredient in traditional Chinese medicine, can mitigate the oxidative stress that helps drive dAMD; however, its low water solubility and poor corneal permeability limit its efficacy. We developed dual-functional polymeric micelles (PMs) co-conjugated with a glycocalyx-binding peptide (GBP) and a cell-penetrating peptide (TAT) for the enhanced topical ocular delivery of quercetin (QUE), named GT-PMs/QUE. The GT-PMs/QUE exhibited a particle size of 46.25 ± 3.05 nm and a zeta potential of -5.64 ± 0.92 mV. GT-PMs exhibited significantly higher cellular uptake efficiency than the unmodified group (PMs) and single-peptide modified groups (GBP-PMs and TAT-PMs). In the sodium iodate-induced oxidative damage model of adult retinal pigment epithelial cell line-19 (ARPE-19) cells, the GT-PMs/QUE treatment group showed significantly reduced ROS and MDA levels along with markedly increased SOD, CAT, and GSH activities that approached normal control levels compared to the model group. In a mouse model of dAMD, GT-PMs/QUE greatly improved the bioavailability of quercetin delivered via eye drop administration and attenuated sodium iodate-induced retinal damage. This study provides a theoretical and experimental basis for enhanced ocular delivery of quercetin and protection against dAMD-related retinal damage.