Abstract

Under metabolic disorders such as diabetes, the regenerative capacity of bone tissue is compromised, characterized by hyperglycemia-induced oxidative stress, impaired osteogenesis, and dysregulated angiogenesis. These complications undermine the efficacy of conventional bone repair materials, limiting their capacity to promote effective healing. Herein, we developed a metal–flavonoid functionalized coating strategy that integrates osteogenic and angiogenic metal ions with natural antioxidant flavonoids. Leveraging their chelation ability and strong surface affinity, a one-pot approach is established to endow conventional bone repair materials with tailored biofunctions that modulate the diabetic bone microenvironment and facilitate regeneration. Among the tested candidates, copper-quercetin (CQ) coating is screened as the optimal formulation owing to its potent antioxidative, osteoinductive, and pro-angiogenic properties under high-glucose (HG) conditions. Conventional bone repair materials (e.g., β-tricalcium phosphate, β-TCP) modified with this coating significantly ameliorated oxidative stress, restored osteogenesis, and rescued angiogenesis impaired by persistent hyperglycemia. In diabetic rats, CQ-coated β-TCP (β-TCP@CQ) accelerated bone healing by 1.68-fold compared to unmodified controls. Mechanistically, the CQ coating activated the ATP7A/SOD3/FLT1 axis to restore copper homeostasis in bone marrow mesenchymal stem cells while stimulating the PI3K-Akt pathway to enhance osteogenic differentiation. Moreover, the coating exhibited broad versatility across multiple biomaterial compositions (metals, ceramics, polymers, and composites) and structures (2D discs, 3D scaffolds). This metal–flavonoid coating strategy demonstrated feasibility and scalability, while also providing a mechanistic foundation and technical platform for the effective use of conventional bone repair materials in complex pathological contexts.