DES-mediated self-assembled polypeptides: Synergistic neuromuscular signaling inhibition for anti-aging.

Skin aging involves complex mechanisms such as overactivation of neuromuscular signals and oxidative stress. Herein, we developed a synergistic transdermal delivery system combining self-assembled tripeptide nanoparticles (DAC-SAPs) and a ternary deep eutectic solvent (DES, betaine-glycerol-propylene glycol, BGP) for anti-aging. DAC-SAP integrates dipeptide diaminobutyryl benzamide diacetate (DDB), argireline (ARG), and μ-conotoxin (CTX) into a single nanostructure through hydrophobic interactions, hydrogen bonds, and electrostatically driven molecular self-assembly. This spatial co-localization ensures synchronous delivery and spatiotemporal synergy, effectively inhibiting neuromuscular signaling. BGP DES optimizes polarity regulation, destroys stratum corneum lipids, and significantly promotes transdermal penetration. Molecular dynamics (MD) simulations reveal a dual permeation-promoting mechanism, with an appropriate nanostructure size reducing transmembrane resistance, whereas DES promotes lipid mobility and weakens tight junctions in the stratum corneum (SC). In vitro, in vivo, and exploratory clinical assessments demonstrate that DAC-SAP/BGP significantly inhibits sodium and calcium channel activity, reduces acetylcholine (ACh) secretion, and improves skin elasticity and wrinkle parameters. This multicomponent system achieves a synergistic anti-aging effect by blocking and enhancing the transmission of neuromuscular signals, thus providing a new strategy for anti-aging skin care.