Peptide-Directed Aqueous-Phase Fabrication of Lipoic Acid Hydrogels for Covalent Protein Loading and On-Demand Release in Wound Healing

Despite their biomedical potential, α-lipoic acid (LA)-based hydrogels face challenges regarding polymerization, stability, and functionalization. Here, we propose a "polymerization-functionalization" strategy for fabricating stable LA-based hydrogels using a bioderived peptide (SpyTag-Cys, ST-Cys) as an initiator. Through multiscale interactions (peptide-monomer, -polymer, and -peptide), ST-Cys drives efficient polymerization of LA monomers under mild aqueous conditions and fortifies the network against hydrolysis while simultaneously providing anchoring sites for covalent protein loading. Integrated with a dual cross-linking of disulfide bonds and dopamine coordination bonds, the peptide-driven framework yields a hydrogel with favorable structural integrity and multifaceted bioactivities, enabling the responsive, sustained release of interleukin-33 in the wound microenvironment. Consequently, it significantly accelerates cell migration and skin wound healing in both in vitro and in vivo models. This study introduces an approach for creating stable functionalized LA-based hydrogels, and the developed "polymerization-functionalization" strategy also offers valuable insights for developing high-performance biomaterials.