Intelligent responsive alloy scaffold temporally regulates the immune-osteogenic axis for the treatment of infectious bone defects

Excessive immune activation induced by persistent bacterial infection, which further impairs osteogenic function, is a crucial factor contributing to the poor healing of infectious bone defects. Therapeutic strategies targeting a single link often yield limited efficacy. Therefore, we developed an alloy scaffold bone graft (TCMP) with pH-responsive sequential regulation of the immuno-osteogenic axis. During the infection phase, the scaffold mainly releases copper ions to exert potent antibacterial activity, and simultaneously releases Pueraria lobata -derived exosome-like nanovesicles (PELNs) in a pH-responsive manner, thereby effectively suppressing the early inflammatory cytokine storm. In the osteogenesis phase, the scaffold switches its release pattern to sustained magnesium ion release, accompanied by low-level sustained release of PELNs, which targets mesenchymal stem cells, vascular endothelial cells and macrophages to promote the directional recruitment and migration of stem cells, accelerate their osteogenic differentiation, improve the inflammatory immune microenvironment and enhance angiogenesis; consistent with the physiological characteristics of extremely scarce osteoclasts in the early stage of implantation, Mg 2+ exerts no regulatory effect on osteoclasts in this study. Mechanistically, TCMP mediates dual-pathway synergistic therapy for infectious bone defects by inhibiting the advanced glycation end products/receptor for advanced glycation end products/nuclear factor-κB (AGEs/RAGE/NF-κB) pathway and activating the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In conclusion, the developed TCMP alloy scaffold integrates the “trinity” functions of antibacterial activity, anti-inflammation, and osteogenesis, comprehensively breaking the vicious cycle of bacterial infection-excessive inflammatory activation-impaired osteogenic capacity, and providing a therapeutic strategy with excellent translational potential for clinical practice.