An immunomodulatory bioactive glass orchestrates early bone healing via coordinated macrophage polarization and osteogenesis-osteolysis balance.

Effective repair of large bone defects remains a major challenge in regenerative medicine. Conventional strategies often emphasize enhancing osteogenesis, while the role of the early immune microenvironment remains insufficiently addressed. Bone regeneration is not merely a structural filling process but a complex physiological program orchestrated by the immune system, requiring a dynamic balance between osteogenesis and osteolysis. Here, we propose an immune-instructive strategy aimed at modulating the early immune response to establish a favorable microenvironment for efficient bone regeneration. Based on this concept, a pH-neutral bioactive glass functionalized with Arginine-Glycine-Aspartic Acid-Serine (RGDS) peptides, designated as NBG@RGDS, was designed and fabricated to achieve synchronized and multi-targeted regulation of the osteoimmune microenvironment. This system concurrently orchestrates three pivotal stages in osteoimmunology including polarizing macrophages toward a pro-repair M2 phenotype, inhibiting excessive osteoclastogenesis and osteoclast activity, and promoting the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Transcriptomic analysis suggested the potential mechanisms through which NBG@RGDS regulates macrophages. In a rat femoral condyle defect model, NBG@RGDS optimized the early immune landscape, effectively attenuated inflammation, and markedly accelerated early-stage new bone formation. This study demonstrates that modulating the initial immune crosstalk represents a more fundamental and efficient strategy for bone regeneration than merely stimulating osteogenesis. It provides a novel perspective for the development of next-generation immunomodulatory bone repair materials.