Dual-Functionalized Hierarchical Peptide Nano-Architectonics for Enhanced Transdermal Delivery and Anti-Aging Applications

Transdermal delivery of therapeutic peptides is limited by their poor permeability and susceptibility to enzymatic degradation. We present a hierarchically engineered water-in-oil-in-water nanoarchitectonic platform that addresses these challenges through dual functionalization and co-assembly-driven stabilization. The system integrates: (i) a co-assembled inner aqueous core of three functionally complementary peptides with a betaine–glycerol deep eutectic solvent (DES), (ii) a polymer mid-layer that provides physical protection and controlled release, and (iii) an outer aqueous layer functionalized with DES and Arg-Gly-Asp to enhance skin penetration via lipid-interacting and integrin-mediated pathways. This architecture significantly improves delivery efficiency, yielding up to 6.79-fold higher cellular uptake and 8.25-fold greater skin permeation compared with peptide assemblies alone. These enhancements correlate with improved in vitro resilience against UV-induced oxidative stress, inflammation, and extracellular-matrix degradation, and with modulation of several aging-related pathways in cellular and Caenorhabditis elegans models. This study demonstrates a materials-centered strategy for stabilizing and delivering peptide therapeutics across the skin barrier. The hierarchical design principles introduced here may serve as a generalizable approach for next-generation transdermal peptide formulations.