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Through multi\u2010omics profiling of clinical IAI samples, we identify lactate as a key metabolite associated with immunosuppression within the biofilm\u2010associated microenvironment of IAIs. Guided by this insight, we engineer a nanotherapeutic platform (LMVM) comprising vacancy\u2010engineered hollow magnetite nanoparticles (VE\u2010HMN) 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\u2010associated infections. Simultaneously, lactate oxidation intensifies local hypoxia, which redirects bacterial metabolism to activate MNZ against tolerant subpopulations while suppressing staphyloxanthin (STX)\u2010dependent antioxidant defenses. As a result, this immunometabolism\u2010guided nanotherapy achieves robust biofilm eradication in murine IAI models and promotes tissue repair. Collectively, these findings identify lactate\u2010mediated immunosuppression as a therapeutically actionable feature of biofilm\u2010associated infections and support a clinically guided materials strategy that couples immunometabolic microenvironment remodeling with the eradication of antibiotic\u2010tolerant biofilms.<\/jats:p>","DOI":"10.1002\/adma.75214","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:08:01Z","timestamp":1790950081000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate\u2010Depleting Nanotherapy Reprograms the Immunometabolic Microenvironment to Overcome Biofilm Tolerance in Implant\u2010Associated Infections"],"prefix":"10.1002","author":[{"given":"Wenbo","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Shanghai Institute of Microsurgery on Extremities Shanghai Sixth People's Hospital Affiliated to 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