Immunomodulation‐Based Multifunctional Decellularized Matrix Bioink Derived from M2 Macrophages Remodels the Bone Microenvironment via Neurogenesis and Angiogenesis

Abstract Events associated with bone healing include early inflammatory immunomodulation, angiogenesis, innervation, bone formation and resorption, where immunomodulation has excellent potential to achieve multisystem regulation in bone tissue engineering (BTE). However, immunomodulatory strategies encompassing key stages in bone repair remain unreported. Macrophages are increasingly recognized as key regulators of tissue regeneration and may be pivotal in efficiently integrating bone grafts with the immune, vascular, and nervous systems. Proteomics reveal that proteins associated with osteogenesis, angiogenesis, and neurogenesis are enriched in M2 macrophages. To safely and effectively use multifunctional M2 macrophages in BTE, a multifunctional bioink (GOM2‐DM) is developed by incorporating an M2 macrophage decellularized matrix (M2‐DM) into a xyloglucan oxide–gelatin methacryloyl (OXG–GelMA) hydrogel, which is 3D‐printed with polycaprolactone‐nano‐hydroxyapatite (PCL‐nHAP) scaffolds for cranial defect regeneration. In critical‐sized defects, early OXG/M2‐DM synergy optimizes the M1‐to‐M2 transition and resolves inflammation on schedule, establishing a prerequisite for subsequent healing. During repair progression, GOM2‐DM stimulates H‐type angiogenesis and neuronal‐specific proteins (β3‐Tubulin/NeuN). Ultimately, GOM2‐DM enhances bone mass formation and achieves good integration between the host and graft. It is further demonstrated that M2‐DM activates the PI3K/AKT pathway via IGF1 secretion to promote BMSC osteogenesis. This immunomodulation‐based strategy coordinates the bone niche holistically, demonstrating significant translational potential for BTE.