Osteoimmunoengineering With Exosome-Functionalized Biomaterials: Rewriting the Immune-Bone Regeneration Interface.
Bone regeneration is a highly coordinated, multistep process governed by interactions among skeletal cells, immune components, and the vascular system. Although bone exhibits an intrinsic capacity for self-repair, critical-sized defects caused by trauma, tumor resection, infection, or chronic diseases often exceed this regenerative potential and necessitate therapeutic intervention. Conventional bone tissue engineering strategies have predominantly focused on promoting osteogenesis and angiogenesis; however, their limited clinical translation indicates that essential regulatory mechanisms remain insufficiently addressed. Advances in osteoimmunology have revealed that immune responses-particularly the initiation, intensity, and resolution of early inflammation-play an instructive role in determining bone healing outcomes. In parallel, exosomes have emerged as mediators of intercellular communication, capable of transferring bioactive cargos that regulate immune cell polarization, angiogenesis, and osteogenic differentiation. Integrating exosomes with biomaterial scaffolds has led to the concept of osteoimmunoengineering, in which scaffolds are designed not only to provide mechanical support but also to modulate the immune microenvironment in a spatiotemporally controlled manner. This review systematically discusses how exosome-functionalized biomaterials can reprogram immune responses to enhance bone regeneration. We outline the immune landscape of bone healing, highlighting key immune cell populations and cytokine signaling pathways involved in inflammation resolution and tissue reconstruction. We also examine immunomodulatory mechanisms of exosomes, material-based strategies for regulating exosome immobilization and release kinetics, and major translational challenges, including exosome heterogeneity, manufacturing standardization, and clinical product classification.