Endogenous Metal Ion‐Enriched Immunostimulating Biomimetic Scaffold Improves In Situ Bone Regeneration

Effective in situ regeneration and functional reconstruction of large-scale bone defects remain a formidable clinical challenge. The endogenous metal ions have been shown to critically regulate immune responses and bone remodeling, but methods for precisely regulating the spatiotemporal recruitment dynamics of endogenous ions are still lacking. Here, we develop a novel endogenous metal ion-enriched immunostimulation-amplified bone biomimetic scaffold (emia-BBS) based on the hierarchical multi-level assembly of nano-hydroxyapatites (nHAs), collagen fibrils, and mussel adhesion proteins (MAPs). The emia-BBS not only mimics the nanostructure and mechanical properties of native bone, but notably, the assembled MAPs endow emia-BBS with abundant lysine and dopamine chemical structures, enabling efficient capture of endogenous metal ions to amplify ion-mediated immunomodulation. Functionally, in large-scale mandibular defects, emia-BBS-induced enrichment of endogenous metal ions could recruit and reprogram macrophages, thereby enhancing the innate immune response. These M2 macrophages, recruited by the emia-BBS-metal ion complex, in turn, facilitate the recruitment and osteogenic activation of endogenous LepR⁺ skeletal stem cells via the CCL5/CCR5/STAT3 axis. This study introduces an immunomodulatory strategy that harnesses endogenous ion dynamics to amplify regenerative signals, providing a precisely guided and clinically applicable approach for critical-sized bone defect repair.