From Lipid Composition to Electroporation: Mechanical Encoding of Barrier Resilience in Stratum Corneum Membranes.

The permeability of the skin barrier is not fixedit emerges from the molecular organization of its lipid matrix. In the stratum corneum, compositional alterations associated with dermatological conditions reshape this organization, yet how these changes influence electrically induced transport remains unclear. Here, we employ fully atomistic nonequilibrium molecular dynamics simulations to uncover how lipid composition is mechanically encoded into electroporation response in biomimetic SC lipid membranes. Eleven membrane models spanning ceramide-rich, cholesterol-rich, and physiologically balanced compositions were systematically investigated. We find that electroporation susceptibility is not dictated by individual lipid species but by the collective mechanical state encoded in membrane packing. Cholesterol-rich membranes exhibit rapid pore nucleation and form large conductive defects, whereas ceramide-dominated systems resist pore formation within the simulated time scale. Intermediate compositions display delayed nucleation and reduced pore sizes. The physiologically balanced SCbase membrane exhibits delayed pore formation and comparatively small conductive defects, consistent with a mechanically resilient yet not pore-immune regime. By linking pore nucleation events and time-resolved water transport to equilibrium structural descriptors, we show that bilayer thickness, interfacial cohesion, and lipid organization collectively define the effective barrier to defect formation. These results establish a predictive framework connecting compositional alterationsrelevant to both healthy and compromised skinto electrically induced permeability, providing molecular-level insights into barrier resilience and strategies for controlled transdermal transport.