Lactate-Depleting Nanotherapy Reprograms the Immunometabolic Microenvironment to Overcome Biofilm Tolerance in Implant-Associated Infections.

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.