Congener‐Induced Sulfur‐Related Metabolism Interference Therapy Promoted by Photothermal Sensitization for Combating Bacteria

Abstract Metabolic homeostasis is vital for individual cells to keep alive. Stronger metabolic homeostasis allows bacteria to survive in vivo and do persistent harm to hosts, which is especially typical in implant‐associated infection (IAI) with biofilm intervention. Herein, based on the competitive role of selenium (Se) and sulfur (S) in bacteria metabolism as congeners, a congener‐induced sulfur‐related metabolism interference therapy (SMIT) eradicating IAI is proposed by specific destruction of bacteria metabolic homeostasis. The original nanodrug manganese diselenide (MnSe₂) is devised to generate permeable H₂Se in bacteria, triggered by the acidic microenvironment. H₂Se, the congener substitution of H₂S, as a bacteria‐specific intermediate metabolite, can embed itself into the H₂S‐utilization pathway and further alternatively disrupt the downstream sulfur‐related metabolism state inside bacteria. A proteomic study indicates ribosome‐related proteins are heavily downregulated and the basic metabolic pathways are mainly disordered after SMIT, revealing the destruction of bacteria metabolic homeostasis. The efficiency of SMIT is significantly promoted with the mild temperature sensitization provided by the photothermal treatment (PTT) of MnSe₂ nanoparticles, verified by the proteomic study and the anti‐IAI effect in vitro and in vivo. With the intelligent nanodrug, a PTT‐promoted SMIT strategy against IAI is provided and a new insight into the interference design toward metabolic homeostasis with biochemical similarity is demonstrated.