Cu²⁺-chelated epigallocatechin gallate nanoparticle-functionalized hydrogel promotes osteogenesis by inhibiting...

A pathological inflammatory microenvironment can hinder bone regeneration by disrupting the osteogenic differentiation potential of bone marrow-derived mesenchymal stem cells (BMSCs). However, conventional anti-inflammatory therapies alone are insufficient to fully resolve this challenge. Bone defect repair is often impaired by persistent inflammation-induced ferroptosis in BMSCs, and traditional approaches fail to prevent lipid peroxidation-driven cell death. Thus, targeting ferroptosis through lipid metabolic reprogramming and redox homeostasis restoration has emerged as a promising therapeutic strategy. Here, we present a reactive oxygen species (ROS)-responsive hydrogel (GGBH@EAC) featuring EGCG-Arg-Cu (EAC) nanoparticles and nano-hydroxyapatite (nHAp) within a dual-network system composed of gelatin methacryloyl (GelMA), cationic guar gum (CG), and borax. EAC inhibits ferroptosis by reprogramming lipid metabolism and restoring redox homeostasis, while nHAp provides essential mineral components for bone regeneration. Boronate ester bonds in the dual-network hydrogel are cleavable under high-ROS conditions, enabling controlled nanoparticle release. In vitro, GGBH@EAC scavenged ROS, alleviated mitochondrial damage, and promoted monounsaturated fatty acid synthesis, thereby suppressing ferroptosis and enhancing BMSC osteogenic differentiation. Multi-omics analysis indicated that these effects were mediated by stearoyl-CoA desaturase 1 (SCD1)-driven lipid metabolic reprogramming and the restoration of redox homeostasis resulting from the downregulation of NADPH oxidase 1 (NOX1) and cytochrome P450 (CYP). In a rat critical-sized bone defect model, GGBH@EAC achieved near-complete bone repair and robust vascularization without systemic toxicity within 8 weeks. This work establishes a translational platform that directs cellular metabolic fate against stress-induced death, as exemplified by the inhibition of ferroptosis to unlock bone regeneration.