Abstract
ABSTRACT
Biofilm formation in implant‐associated infections (IAIs) establishes an immunosuppressive microenvironment while conferring profound antibiotic tolerance. Through multi‐omics profiling of clinical IAI samples, we identify lactate as a key metabolite associated with immunosuppression within the biofilm‐associated microenvironment of IAIs. Guided by this insight, we engineer a nanotherapeutic platform (LMVM) comprising vacancy‐engineered hollow magnetite nanoparticles (VE‐HMN) coloaded with lactate oxidase (LOX) and metronidazole (MNZ). By depleting lactate, LMVM remodels the immunosuppressive microenvironment and restores antimicrobial immunity, thereby highlighting lactate as an immunometabolic regulator in biofilm‐associated infections. Simultaneously, lactate oxidation intensifies local hypoxia, which redirects bacterial metabolism to activate MNZ against tolerant subpopulations while suppressing staphyloxanthin (STX)‐dependent antioxidant defenses. As a result, this immunometabolism‐guided nanotherapy achieves robust biofilm eradication in murine IAI models and promotes tissue repair. Collectively, these findings identify lactate‐mediated immunosuppression as a therapeutically actionable feature of biofilm‐associated infections and support a clinically guided materials strategy that couples immunometabolic microenvironment remodeling with the eradication of antibiotic‐tolerant biofilms.