Mg-MOF-74 incorporation remodels the regenerative microenvironment and enhances bone regeneration in a collagen–hydroxyapatite scaffold

Introduction Incorporation of magnesium has been widely adopted to improve the performance of bone biomaterials, yet the biological processes underlying these benefits remain incompletely understood. Methods We developed a Mg‐MOF‐74‐incorporated collagen‐hydroxyapatite scaffold (Mg‐PHA‐COL) and systematically evaluated its material properties and biological responses using in vitro characterization, subcutaneous implantation, transcriptomic profiling, RT‐qPCR, and a rat critical‐sized cranial defect model. Results Mg‐PHA‐COL exhibited a porous architecture, Mg 2 ⁺ release, improved mechanical properties, and enhanced cytocompatibility. In a subcutaneous implantation model, it promoted vascular infiltration and tissue remodeling compared with the control scaffold. Transcriptomic profiling identified distinct regenerative transcriptional changes, with the PKG signaling pathway among the most significantly enriched pathways. RT‐qPCR further confirmed differential expression of selected genes associated with the PKG signaling pathway, together with changes in genes related to tissue repair, vascular infiltration, and osteogenesis. In the rat cranial defect model, Mg‐PHA‐COL significantly enhanced new bone formation, vascularization, and mineralization. Discussion These findings suggest that Mg‐MOF‐74 incorporation improves scaffold performance and is associated with a favorable regenerative microenvironment, while transcriptomic analysis provides insight into the biological responses accompanying enhanced bone regeneration.