Recent progress in immunomodulation-based strategies for bone repair

Bone regeneration is a highly coordinated process shaped by the interplay between immune responses and osteogenic mechanisms. Immune cells such as neutrophils, macrophages, T cells, and B cells dynamically regulate the local microenvironment through cytokine secretion and signaling pathways, thereby influencing osteogenesis, angiogenesis and bone remodeling, while dysregulated or prolonged inflammation can disrupt healing. Growing evidence has highlighted the potential of leveraging immunomodulation to enhance bone repair. This review synthesizes recent progress in immunoregulatory strategies by comparing cellular therapies, molecular interventions and biomaterial-based approaches in terms of their mechanisms, their effects on osteogenesis and angiogenesis, and their translational potential. Particular emphasis is placed on immune cell specific signaling pathways, biomaterial design parameters including surface topography, porosity, ion release and stiffness, and emerging technologies such as immune responsive hydrogels, programmable scaffolds and exosome based delivery systems. Current findings indicate that mesenchymal stem cells and regulatory T cells not only provide progenitor sources but also reshape the immune milieu through paracrine factors and exosomes; cytokines, small molecules, microRNAs and pro resolving mediators effectively modulate inflammatory cascades to promote vascularized bone formation; and immunomodulatory biomaterials enable spatiotemporal regulation of macrophage polarization, particularly the transition from the pro inflammatory M1 phenotype to the reparative M2 phenotype. Collectively, these advances highlight that bone repair is fundamentally an immunologically driven process, and integrating temporal immune regulation with emerging therapeutic platforms offers a promising pathway toward precise and personalized bone regeneration.