Biomimetic liposomal co-delivery of quercetin and carnosine for enhanced transdermal penetration and NRF2/HES1-mediated antioxidant photoprotection

Quercetin and carnosine, natural antioxidants with anti-aging and photoprotective potential, face therapeutic limitations due to poor skin permeability. We engineered EV-QuerCar, a liposomal-based nanoparticles (LPNs) system co-encapsulating both compounds, to enhance transdermal delivery and evaluate its structural and functional efficacy. EV-QuerCar was prepared biomimetically using thermophilic bacterial lipids via ultracentrifugation, thin-film hydration, and high-pressure homogenization. Physicochemical properties, transdermal penetration, cellular uptake, and cytotoxicity were tested in vitro. Molecular docking and qPCR assessed pathway targeting. EV-QuerCar exhibited uniform size (94.70 ± 0.71 nm), high encapsulation efficiency (90.07%), sustained release, and 3.21-fold enhanced transdermal absorption compared to free compounds. Cellular uptake in fibroblasts increased time-dependently (up to 5.48-fold at 4 h). Molecular docking and qPCR confirmed interactions with NRF2 and HES1 targets, significantly upregulating their mRNA levels (2.29- and 3.35-fold, respectively) in UV-exposed human fibroblasts. EV-QuerCar improves skin permeability and antioxidant efficacy, highlighting its cosmeceutical promise.