Cysteine Metabolism Reprogramming-Motivated Catalytic Immunotherapy for Orthopedic Biofilm Infections

Immunotherapeutic strategies have proven to be very promising in the treatment of drug-resistant infections. However, breakthroughs against medical implant infections have been hampered by the presence of sophisticated bacterial biofilm defense barriers and suppressive immune cells at the biofilm–immune interface. Herein, we developed a nanointerfering catalyst (niCatalyst) for targeted modulation of cysteine metabolic processes in the biofilm–immune microenvironment (BIME). By releasing aurin tricarboxylic acid, the niCatalyst effectively blocked key enzymes involved in cysteine metabolism, thus limiting the production of hydrogen sulfide and glutathione in the biofilm defense barrier. Light-triggered burst catalysis of singlet oxygen further exacerbated the oxidative stress damage within the biofilm. Additionally, interference with cysteine metabolism inhibited cellular glutathione synthesis, leading to the enhancement of antimicrobial immune responses and antigen-presenting cell functions in macrophages. This, in turn, costimulated the immune functions of antibiofilm adaptive helper T cells and cytotoxic NK cells. In summary, our emerging niCatalysts enable reprogramming of cysteine metabolism in the BIME, as well as costimulation of innate and adaptive immunotherapy. This approach effectively eliminates drug-resistant biofilm infections with low metabolic activity, providing an alternative for metabolic immunotherapy in the postantibiotic era. © 2025 American Chemical Society.