Cationic Corona-Engineered Polymer–Lipid Hybrid Nanoparticles for Enhanced Dermal Penetration and Cellular Bioavailability

Cationic polymer–lipid hybrid nanoparticles were engineered to overcome cytotoxicity limitations of conventional surfactants while achieving enhanced skin penetration and controlled drug release. Poly(2-ethyl-2-oxazoline)- block -poly(ε-caprolactone) (POx- b -PCL) copolymers were synthesized via ring-opening polymerization and coassembled with lecithin through nanoprecipitation, yielding spherical nanoparticles (∼120 nm). Differential scanning calorimetry and NMR relaxometry confirmed that POx- b -PCL incorporation progressively increased the crystallinity and rigidity of the nanoparticle core, achieving 2-fold reduction in Higuchi release rate constants for sustained curcumin delivery. Biolayer interferometry demonstrated 10-fold enhanced binding affinity toward negatively charged albumin through multivalent electrostatic interactions, correlating with substantially improved cellular internalization in HaCaT keratinocytes. Confocal microscopy of ex vivo porcine skin revealed 70% increased transdermal penetration depth, with maximum fluorescence at 30–40 μm beneath the stratum corneum. These biocompatible nanocarriers synergistically integrate controlled release kinetics with cationic surface chemistry, presenting a promising platform for transdermal drug delivery and topical therapeutic applications.