Immune and Stem Cell‐Mediated Bactericidal Amplification and Bone Remodeling for Infection Clearance and Osteointegration

ABSTRACT Implant‐related infections reduce mesenchymal stem cell accumulation near implant sites while suppressing the viability and osteogenic capacity of these stem cells. Here, we show that pH‐responsive biomaterial interfaces exploit infection‐induced acidification to coordinate antimicrobial action with stem and immune cell functional reprogramming. The system can release bactericidal peptides for direct bacterial elimination, whereas indirect bactericidal enhancement occurs in the presence of magnesium ions and cell‐targeting peptides, which enable a positive modulation of immune responses and recruitment of bone marrow mesenchymal stem cells, respectively. This feature results in robust osteogenic differentiation at the implant interfaces, achieving a 280% increase in the interfacial bone volume in rat infection models. Through transcriptomic analysis, we also show that Wnt‐activated stem cells and alternatively activated macrophages jointly upregulate antimicrobial effector programs along with osteogenic genes, contributing to the observed >4‐log bacterial reduction through combined material‐ and cell‐mediated suppression. The coordinated infection clearance and interface regeneration demonstrate that infection‐responsive biomaterials can transform endogenous cells to bifunctional therapeutic agents, defining a strategy that addresses infection and regeneration as integrated biological processes.