A Synergistically Engineered Protein Hydrogel Integrating Topological Reinforcement and Metal‐Ion Coordination for Diabetic Wound Repair

ABSTRACT The clinical translation of extracellular matrix (ECM)‐mimetic protein hydrogels is often hampered by their inadequate mechanical strength and structural disorder. Innovative strategies that integrate structural control with bioactive cues are urgently needed for diabetic wound repair. We present a synergistic “topological engineering/metal‐coordination” strategy to design a new class of collagen‐like protein hydrogels. Via genetic encoding, metal‐binding domains (Zn 2 + , Ag + , Cu 2 + ), together with a cell‐adhesive RGD motif and stabilizing Vα/Vβ domains, were incorporated into collagen scaffolds (CLP3/CLP1). We further engineered hydrogels with precisely defined point‐, cyclic‐, and bis‐cyclic‐crosslinked topologies. The Zn 2 + ‐coordinated, bis‐cyclic‐crosslinked hydrogel based on CLP3 (BZnCα3) exhibited optimal integrated performance. It demonstrated skin‐like stress‐strain curves, superior toughness, and excellent fatigue resistance. In vitro, BZnCα3 promoted cell adhesion, proliferation, migration, and exhibited potent antibacterial and anti‐inflammatory effects. In a diabetic mouse model, BZnCα3 significantly accelerated wound closure, enhanced re‐epithelialization and collagen deposition, and orchestrated a pro‐healing microenvironment by polarizing macrophages to the M2 phenotype, upregulating regenerative factors, and alleviating oxidative stress. This work establishes a genetically encoded platform for creating protein hydrogels with tunable topology and dynamic mechanics, emerging as a multifaceted biomaterial that effectively addresses mechanical and biological barriers, holding great promise as a therapeutic dressing for refractory diabetic wounds.