Osteoradionecrosis of the jaw (ORNJ) is a severe late complication of radiotherapy driven by vascular injury, hypoxia, fibrosis, persistent inflammation, and impaired bone remodeling. A recent study demonstrated that human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) improve ORNJ repair by restoring osteogenic differentiation of irradiated bone marrow mesenchymal stem cells through PI3K/AKT signaling and enhancing endothelial angiogenic activity through Wnt/β-catenin signaling. These findings establish an important regenerative framework but leave the immune compartment largely unexplored. We propose that macrophages represent a critical mechanistic link between hAMSC-sEV therapy and coordinated tissue repair. By reprogramming radiation-dysregulated macrophages toward pro-resolving, reparative phenotypes, hAMSC-sEVs may suppress chronic inflammation while simultaneously supporting osteogenesis and neovascularization. Defining the extracellular-vesicle cargo and macrophage signaling networks responsible for this effect could advance osteoimmunology-informed strategies and improve the translational development of cell-free therapies for ORNJ. This perspective highlights priorities for experimental validation and future clinical translation.
