Coordination‐Driven Cu 2+ ‐Peptide Supramolecular Hydrogel‐PCL Scaffold for Synergistic Antibacterial Activity and Osteogenic Regeneration in Infectious Bone Defects

ABSTRACT Infectious bone defects, characterized by persistent bacterial infection and impaired osteogenesis, remain a major clinical challenge. Here, a copper ion‐peptide supramolecular hydrogel integrated with a 3D‐printed polycaprolactone scaffold (CPSH@PCL) was developed for synergistic treatment of infectious bone defects. Cu 2+ ‐mediated peptide coordination formed a stable nanofibrous network, enabling robust scaffold coating, enhanced mechanical support, and sustained Cu 2+ release under both physiological and infection‐associated mildly acidic conditions. CPSH@PCL exhibited potent broad‐spectrum antibacterial and antibiofilm activity (>99% against methicillin‐resistant Staphylococcus aureus and Pseudomonas aeruginosa ) and disrupted mature biofilms. It also scavenged reactive oxygen species and catalyzed oxygen generation, alleviating infection‐induced oxidative stress and hypoxia. At the cellular level, CPSH@PCL promoted proliferation and migration of bone marrow mesenchymal stem cells and osteoblasts, while markedly enhancing osteogenic differentiation through activation of HIF‐1α‐mediated aerobic glycolysis. In a rat cranial defect model, CPSH@PCL suppressed infection, significantly increased bone mineral density and bone volume fraction, and accelerated new bone formation with upregulated osteocalcin. This work demonstrated a metal ion‐driven peptide self‐assembly strategy that integrated antibacterial, antioxidant, and osteogenic functions in a single scaffold, offering a multifunctional biomaterial platform for treating complex infectious bone defects.