Magnesium ion hydrogel enhances resistance to radiation-induced bone injury by modulating the bone immune...

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 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.