Trained Decoy Nanocages Confer Selective Cuproptosis and Metabolic Reprogramming for Drug-Resistant Bacterial Targeting Therapy.

Nonantibiotic strategies are urgently needed to treat acute drug-resistant bacterial pneumonia. Recently, nanomaterial-mediated bacterial cuproptosis has arisen widespread interest due to its superiority against antibiotic resistance. However, it may also cause indiscriminate and irreversible damage to healthy cells. Here, we synthesized trained decoy mCuS@lm nanocages, consisting of trained membranes, copper sulfide, mitoquinone, and luteolin for selective cuproptosis and targeted therapeutic strategies. The nanocages could amplify bacterial cuproptosis through quorum sensing inhibition that cuts off bacterial interactions and modulates virulence factors and biofilm formation. Meanwhile, the nanocages could protect cells from cuproptosis-induced damage through mitochondrial-targeted antioxidants. Trained biomimetic membranes facilitated broad-spectrum bacterial targeting ability and functioned as a decoy to neutralize cytokine storms during pneumonia. Moreover, the nanocages could reprogram the metabolic conditions of both bacteria and host cells. In conclusion, the nanocages provide an approach to treat challenging drug-resistant bacterial pneumonia.