Biomaterials that passively and actively target macrophages promote the regeneration of injured tissues

Modulation of the immune system has gained significant attention in regenerative medicine. Although most tissues possess intrinsic self-repair capabilities, large-sized defects and complex pathological conditions may still lead to tissue microenvironment imbalance and repair failure. Researchers have applied macrophage-mediated immunotherapeutic strategies to various injured tissue repairs by modulating inflammatory responses, intercellular communication, and multitissue synergies to restore immune microenvironmental homeostasis and promote tissue regeneration. Ongoing advancements in materials science have highlighted the precise immunomodulatory role of biomaterials, with passive targeting strategies based on the material's physicochemical properties and active targeting strategies based on specific molecular modifications becoming increasingly important in research. This review focuses on the mechanisms of action of actively and passively targeted biomaterials to modulate macrophages, which improve the tissue regenerative microenvironment through four basic strategies: (i) modulation of the inflammatory response to remove damaged cells, cellular debris, and pathogens; (ii) remodeling of the extracellular matrix; (iii) reconstruction of vascular tissues; and (iv) macrophage-stem cell crosstalk. This review covers the major mechanisms of macrophage action in the regeneration of injured tissues, while exploring the multiple methods by which advanced biomaterials target macrophages and highlighting their applications in the regeneration of a wide range of tissue injuries. We further discuss the future directions and current limitations in the development of biomaterials for macrophage modulation, aiming to advance biomaterials targeting macrophages, realize the full potential of immunotherapy, and achieve precision medicine.