Orchestrating bone healing: biomaterial-driven immunoengineering of the bone microenvironment for advanced regenerative therapies

Bone regeneration is a multistage and tightly regulated process driven by coordinated interactions between the immune and skeletal systems. While inflammation is essential for initiating repair, its dysregulation contributes to delayed union, nonunion, and impaired healing commonly seen in trauma, chronic disease, and aging. Traditional interventions, including autografts and inert biomaterials, provide structural support but fail to engage or modulate the immune microenvironment that governs successful regeneration. Emerging research in osteoimmunology has revealed the centrality of immune cell populations such as macrophages, T regulatory cells, dendritic cells, and myeloid-derived suppressor cells in directing osteogenesis, angiogenesis, and the resolution of inflammation. Distinct from prior reviews, we integrate temporal immune maps of fracture healing with design rules for phase-specific, programmable biomaterials to guide macrophage and T cell responses toward regeneration. This review synthesizes current understanding of the cellular events and immune phenotypes active throughout the phases of bone healing, highlights pro-regenerative immune subsets and their mechanisms, and examines immunomodulatory drugs and biologics that can reshape the bone microenvironment. Particular emphasis is placed on biomaterial-driven immunoengineering strategies, including hydrogels, scaffolds, microparticles, nanoparticles, and gene-activated matrices designed for localized and spatiotemporally controlled delivery of immunomodulatory cues. Finally, the review outlines critical gaps in the field, including the need for phase-specific immune modulation, high-resolution spatial mapping of immune-bone interactions, and standardized translational frameworks for programmable biomaterials. Together, these insights establish a foundation for next-generation, immune-instructive regenerative therapies capable of orchestrating robust and functional bone repair.