Rational Design and Characterization of 5-Fluorouracil-Loaded Lipid-Polymer Hybrid Nanoparticles for Enhanced Transdermal Delivery in Skin Cancer Therapy.

Effective management of skin cancer remains challenging due to limited transdermal drug penetration, systemic toxicity, and therapeutic resistance. In this study, 5-fluorouracil (5-FU)-loaded lipid-polymer hybrid nanoparticles (LPHNPs) were rationally engineered as a next-generation nanocarrier system to overcome these barriers. The hybrid design synergistically combines the structural integrity of polymers with the biocompatibility and permeability-enhancing attributes of lipids. Using a central composite design, formulation parameters were optimized to achieve favorable physicochemical characteristics, yielding nanoparticles with a mean diameter of 256.7 nm, a polydispersity index (PDI) of 0.2711, and a positive zeta potential of +25.47 mV, indicative of excellent colloidal stability. In vitro release and ex vivo permeation studies revealed a sustained drug release profile and significantly improved dermal penetration compared to conventional formulations. Moreover, the Hen's egg test-chorioallantoic membrane (HET-CAM) irritation assay confirmed the biocompatibility and reduced irritation potential of the developed system. Overall, the optimized 5-FU-loaded LPHNPs present a promising platform for localized, controlled transdermal chemotherapy, potentially minimizing systemic exposure and improving therapeutic efficacy in skin cancer management.