Ferroptosis targeted metal-phenolic nanocomposite hydrogel for immune microenvironment guided regeneration of diabetic bone defects.

Abstract

Diabetic bone defects are not merely a consequence of impaired bone formation, but a complex syndrome driven by chronic hyperglycemia, characterized by dysregulated bone metabolism, vascular impairment, immune imbalance, and notably, aberrant activation of ferroptosis in osteoblasts. These multifaceted pathologies pose a major challenge in orthopedic treatment. In this study, we report the development of a metal-polyphenol synergistic hydrogel platform (HES) designed to address the unique demands of diabetic bone regeneration. Epigallocatechin gallate (EGCG) and strontium ions (Sr²⁺) are self-assembled into bioactive metal-phenolic network (MPN) nanoparticles (EGCG-Sr²⁺ NPs), which are uniformly integrated into a three-dimensional hyaluronic acid (HA) hydrogel matrix. This platform achieves spatiotemporal coordination of EGCG-mediated antioxidation and Sr²⁺-driven angiogenesis, while EGCG chelates metal ions to inhibit ferroptosis by scavenging ROS, sequestering Fe³⁺, protecting GPX4, upregulating HO-1, and suppressing lipid peroxidation. Additionally, EGCG exerts anti-inflammatory effects, and Sr²⁺ promotes angiogenesis, collectively enhancing osteogenic differentiation and tissue repair. Overall, this multifunctional hydrogel integrates ferroptosis inhibition, antioxidation, immunomodulation, and osteoinduction, offering a promising therapeutic strategy for effective repair of diabetic bone defects.