Enhanced Immune Modulation and Bone Tissue Regeneration through an Intelligent Magnetic Scaffold Targeting Macrophage Mitochondria

Abstract During the bone tissue repair process, the highly dynamic interactions between the host and materials hinder precise, stable, and sustained immune modulation. Regulating the immune response based on potential mechanisms of macrophage phenotypic changes may represent an effective strategy for promoting bone healing. This study successfully constructs a co‐dispersed pFe₃O₄‐MXene nanosystem by loading positively charged magnetite (pFe₃O₄) nanoparticles onto MXene nanosheets using electrostatic self‐assembly. Subsequently, this work fabricates a biomimetic porous bone scaffold (PFM) via selective laser sintering, which exhibit superior magnetic properties, mechanical performance, hydrophilicity, and biocompatibility. Further investigations demonstrate that the PFM scaffold could precisely and remotely modulate macrophage polarization toward the M2 phenotype under a static magnetic field, significantly enhancing osteogenesis and angiogenesis. Proteomic analysis reveal that the scaffold upregulates Arg2 expression, enhancing mitochondrial function and accelerating oxidative phosphorylation, thereby inducing the M2 transition. In vivo experiments validated the scaffold's immune regulatory capacity in subcutaneous and cranial defect repairs in rats, effectively promoting new bone formation. Overall, this strategy of immune modulation targeting macrophage metabolism and mitochondrial function offers novel insights for material design in tissue engineering and regenerative medicine.