Interface-engineered supramolecular collagen peptide nanocapsules for barrier repair and matrix remodeling: From molecular assembly to clinical translation

The transdermal delivery of hydrophilic low-molecular collagen peptides (MW ∼5 kDa,) remains a major dermatological barrier, owing to the strong barrier function of the stratum corneum. While recombinant collagen peptides holds significant therapeutic promise, its application is severely limited by poor penetration and susceptibility to enzymatic degradation. Herein, we present an interface-engineered strategy based on a therapeutic supramolecular solvent to overcome these limitations. We constructed a supramolecular collagen peptides nanocapsules (Supra-Coll-Nano) system via the non-covalent assembly of α-bisabolol and dipalmitoyl hydroxyproline (DPHP). Unlike conventional inert carriers, this lipid-based supramolecular solvent not only stabilizes recombinant human type III collagen peptides (rhCOL3A1) through precise interfacial modulation but also synergistically regulates the skin microenvironment. The Supra-Coll-Nano exhibited exceptional physicochemical stability and achieved a 22.43-fold increase in viable epidermis collagen peptides deposition compared to free collagen peptides, penetrating to a depth of ∼40 μm within 8 h, corresponding to deep viable epidermis. Mechanistically, the system activates the TGF-β1/Smad3 signaling pathway, orchestrating the upregulation of a broad spectrum of collagens (types I, III, IV, VII, XVII, XVIII) and key barrier-associated proteins (Filaggrin, Loricrin), while simultaneously suppressing pro-inflammatory cytokines (TNF-α, IL-1α) via the release of bioactive α-bisabolol. Clinical efficacy evaluations further confirmed these pleiotropic effects, demonstrating significant improvements in stratum corneum hydration (+38.38%) and skin elasticity (+21.57%), along with a remarkable 53.94% reduction in crow's feet wrinkles. This work establishes a new paradigm for “carrier-active” synergistic delivery, offering a robust material strategy for sensitive skin repair and non-invasive anti-aging therapies from molecular design to clinical application.