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.