Harnessing Flavonoids for Transdermal Enhancement: Sustainable Strategies to Improve the Permeability of Hydrophilic Drugs through the Transformation of Keratins and Lipids

This study addresses the challenge of transdermal delivery of hydrophilic drugs by evaluating 20 biocompatible compounds as alternatives to synthetic chemical penetration enhancers (PEs). These compounds demonstrated enhanced caffeine permeability in vitro and in vivo, with glabridin and butein showing exceptional performance, achieving a transdermal enhancement ratio close to three times. Furthermore, we conducted systematic evaluation of the compounds’ dermal microstructure modulation capabilities and revealed dual pathways of action: In terms of keratin conformational remodeling, through hydrogen bond interactions with skin keratin, these compounds induce structural transitions from α-helix to β-sheet configurations, accompanied by increased irregular coil formation. This molecular rearrangement significantly loosens the keratin network architecture. In terms of stratum corneum lipid reorganization, concurrently, they promote lipid fluidization within the intercellular matrix, effectively reducing the skin barrier’s resistance. This research establishes an innovative paradigm for hydrophilic drug transdermal delivery through the strategic implementation of biocompatible compounds. The identified flavonoid-based enhancers demonstrate exceptional potential for dual applications in both pharmaceutical transdermal systems and cosmetic formulations. More significantly, this work pioneers an evaluative framework that simultaneously addresses biocompatibility requirements and permeation enhancement performance─a crucial advancement in developing transdermal delivery technologies.