Abstract
Abstract UV-induced skin photoaging is a complex pathology driven by oxidative stress and extracellular matrix (ECM) depletion. Although recombinant human collagen (RHC) and epigallocatechin-3-gallate (EGCG) address these mechanisms, their synergy is limited by RHC’ s poor permeability and EGCG’ s instability. Here, we present a supramolecular co-assembly strategy to overcome these barriers. Validated by molecular dynamics simulations, we utilized the intrinsic proline-rich domains of RHC as anchors for EGCG to construct uniform nanospheres (< 100 nm). This architecture sterically shields EGCG, significantly enhancing stability and reducing cytotoxicity. Biologically, the nanospheres restored mitochondrial membrane potential and promoted anti-inflammatory M2 macrophage polarization. In a photoaging mouse model, the nanospheres outperformed monotherapies, effectively reversing epidermal hyperplasia and restoring the Type I/III collagen ratio. This study resolves the delivery-stability paradox of protein–polyphenol therapeutics, offering a potent strategy for regenerating photodamaged skin. Graphical Abstract