Magnesium Ion Hydrogel Enhances Resistance to Radiation-Induced Bone Injury by Modulating the Bone Immune Microenvironment and Promoting Microvascularization

Mandibular radiation-induced bone injury (RIBI) is a common, severe complication of radiotherapy with no effective treatment. The early course is clinically subtle yet pathologically complex: ionizing radiation (IR) rapidly induces microvascular dysfunction, amplifies immune-mediated inflammation, and disrupts bone homeostasis. This complexity, together with safety considerations, hampers therapeutic translation. Magnesium (Mg2+) is an essential bone component whose pro-osteogenic activity is well established; nevertheless, irradiation may remodel the multi-target effects of bioactive ions, and the integrated mechanisms of Mg2+ in bone radiation injury remain to be clarified. Here, we compared local delivery of an Mg2+- crosslinked alginate hydrogel (Mg@Alg) under irradiated versus non-irradiated conditions in rats, and combined macrophage and endothelial cell models to evaluate radioprotective effects and mechanisms. In our study, Mg@Alg attenuated bone loss and apoptosis within 14 days after IR, promoted M2-like macrophage polarization, and improved microvascular density and maturation, thereby contributing to inflammatory microenvironment remodeling. Mechanistically, Mg2+ intervention was accompanied by decreased ferritin, downregulation of Prolyl hydroxylase domain-2 (PHD2), and stabilization of Hypoxia-inducible factor-1α (HIF-1α), together with Vascular endothelial growth factor A (VEGFA) upregulation; these changes were partly reversed by Fe2+, suggesting an iron-dependent, PHD2/HIF-1α-biased modulation that coordinates immune homeostasis and vascular regeneration to improve immune–vascular coupling. Notably, while Mg2+ efficacy appeared enhanced under IR, the effective concentration window narrowed. In sum, peri-radiotherapy, localized, short-term Mg2+ delivery may improve bone tolerance to radiation and mitigate early RIBI. These findings provide an experimental basis for low-risk, clinically translatable bone radioprotective strategies, and expand the application paradigm of magnesium-based materials in radiotherapy protection contexts.