A biomimetic magnesium–hydrogel scaffold with ferroptosis regulatory function for bone defect repair

• A biomimetic composite scaffold was developed by impregnating 3D-printed Mg scaffolds with hydrogel. • The dual-layer design delayed magnesium degradation and enabled sustained Mg 2+ release. • The scaffold significantly promoted osteogenic differentiation and enhanced bone regeneration. • The scaffold synergistically alleviated ferroptosis and mitigated lipid peroxidation. • The scaffold offers a novel multifunctional platform for complex bone defect repair. Segmental bone defects remain a major clinical challenge due to their poor self-healing capacity and disrupted local microenvironments. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical barrier to bone regeneration under pathological conditions such as oxidative stress and iron overload. However, current grafting strategies lack the ability to modulate ferroptosis or adaptively regulate local stress responses. Here, we developed a biomimetic magnesium-hydrogel composite scaffold with ferroptosis regulatory capability. The scaffold integrates a three-dimensional (3D)-printed Mg framework, a dicalcium phosphate dihydrate (DCPD) coating for corrosion control, and a functional hydrogel composed of gelatin grafted with gallic acid (GA) and phosphocreatine (Pcr). This design synergistically slows degradation, buffers pH, and confers antioxidant and iron-chelating functions. In vitro and in vivo results demonstrated that the scaffold alleviates ferroptosis by upregulating GPX4 and SLC7A11, downregulating ACSL4 and TFR1, and activating MAPK/mTOR signaling, while promoting osteogenic differentiation and angiogenesis. Our strategy offers a multifunctional, microenvironment-responsive scaffold that addresses both structural and biological challenges in bone defect repair.