MgFe-LDH nanocomposites incorporated into gelatin methacryloyl /hyaluronic acid methacrylated hydrogels for controlled drug release: Synergistic regulation of angiogenesis−osteogenesis for bone regeneration

Substantial vascularization has emerged as a promising tissue engineering strategy for regenerating critical-sized bone defects. In this study, we developed an injectable smart hydrogel system (GH-LR) by incorporating roxadustat (RD)-loaded MgFe-layered double hydroxide nanoparticles into a gelatin methacryloyl/hyaluronic acid methacrylate (GH) hybrid matrix. This bioactive composite enables the sustained release of therapeutic agents (RD, Mg 2+ , and Fe 3+ ), synergistically promoting angiogenesis–osteogenesis coupling. Comprehensive characterization confirmed the successful synthesis of GH-LR hydrogels with efficient drug encapsulation. In vitro studies demonstrated that GH-LR significantly enhanced endothelial tube formation in human umbilical vein endothelial cells and osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs), attributable to the prolonged release of bioactive molecules. Mechanistic investigations using RNA sequencing revealed activation of the PI3K-Akt pathways in BMSCs treated with GH-LR hydrogels, correlating with enhanced osteogenesis. In vivo , evaluation in a critical-sized calvarial defect model confirmed accelerated bone regeneration, as evidenced by upregulated expression of Runx2 and Col-1. The therapeutic effects stem from the synergistic interplay between locally sustained angiogenesis and osteogenesis induction. This biocompatible GH-LR system collectively represents an innovative approach for reconstructing large bone defects through controlled delivery and spatiotemporal coordination of pro-regenerative cues.