Skin barrier and beyond: From structural blueprint to rational skin-targeted therapeutics.

Abstract

The cutaneous interface represents a sophisticated biophysical barrier, governed by the complex lamellar organization of stratum corneum (SC) lipids. Traditionally viewed through the lens of static Brick and Mortar analogies, modern insights derived from molecular dynamics and cryo-electron microscopy have redefined the SC as a dynamic, tunable system. This review explores the evolutionary trajectory of barrier modeling from the Domain Mosaic to the Sandwich Model and highlights the critical role of ceramide stoichiometry and acyl-chain distribution in maintaining homeostatic integrity. We examine how these biophysical blueprints have catalyzed the development of next-generation transdermal delivery platforms, including ultra-flexible ethosomes, invasomes, and functionalized nanocarriers designed for targeted nucleic acid (mRNA/siRNA) delivery. By integrating surface modifications, such as mannosylated chitosan, with physical enhancement strategies like microneedle arrays, researchers are overcoming historical permeability constraints. Furthermore, the clinical paradigm is shifting toward barrier-targeted interventions that not only bypass but actively repair the SC matrix in chronic inflammatory conditions like atopic dermatitis. Ultimately, this synthesis underscores the transition of skin-targeted therapeutics from empirical formulation toward rational, biophysically-driven design, offering transformative potential for both localized dermatological therapy and non-invasive systemic immunization.

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