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

ABSTRACT 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.