Localized Lipid Delivery Regulates Exogenous Lipid Behavior at Persistent Defects in Stratum Corneum Lipid Bilayers

Abstract Disruption of the stratum corneum (SC) lipid matrix compromises the skin barrier function; however, the molecular mechanisms by which exogenous lipids promote its repair remain unclear. Here, all-atom molecular dynamics (MD) simulations were employed to investigate how initially dispersed lipid molecules and preassembled nanoparticles influence the direct rearrangement behavior of exogenous lipids at a localized defect in ceramide (CER)/cholesterol (Chol)/free fatty acid (FFA) ternary lipid bilayers. The results show that barrier repair efficiency depends strongly on both delivery format and lipid species. Initially dispersed lipids, limited by inefficient random diffusion, exhibit effective local repair but constrained overall efficiency. In contrast, preassembled lipid nanoparticles follow an “adsorption-spreading-reassembly” pathway, where localized high-concentration delivery overcomes diffusional barriers and significantly enhances repair efficiency. The three lipid species exhibit different molecular repair mechanisms at the damage site, governed by their unique molecular structures: CER shows stronger enrichment, FFA displays greater diffusion and dynamic reorganization, and Chol forms a denser and more stable bilayer. This study provides a molecular-level reconstruction associated with barrier repair and offers guidance for developing more effective topical lipid repair formulations.