Ultrasound‐Activated Heterojunction Sonozymes Trigger Bacterium‐Specific Cuproptosis‐Like Death for Enhanced Sonodynamic‐Chemodynamic Therapy of Multidrug‐Resistant Bacterial Infections

Abstract Cuproptosis‐like‐death‐mediated antibacterial therapy has been regarded as a promising treatment strategy for eliminating multidrug‐resistant (MDR) bacteria and stubborn biofilms. However, the release of Cu ions that are not specific to bacteria can trigger cuproptosis and lead to irreversible damage to healthy tissues. Herein, carbon dots (CDs) with triplet‐mediated sonodynamic activity are deposited on cuproptosis inducer (Cu 2 O) to achieve the multiple amplification effects of antibacterial and antibiofilm activities. First, the sonodynamic and chemodynamic activities of single‐component sonosensitizers/nanozymes are significantly augmented by the formation of heterojunction sonozymes. Second, Cu 2 O/CD with bacterial microenvironment (BME)‐responsive degradation features realizes the bacterium‐specific release of Cu + , CDs, and Cu 2+ , which can not only achieve cascade amplification of reactive oxygen species (ROS) production through depleting GSH but also realize the bacterium‐specific cuproptosis‐like death. Notably, transcriptome sequencing analysis indicates that Cu 2 O/CD‐mediated combination therapy damaged bacterial ribosomes and ion transport, facilitating the influx of Cu ions and disrupting the bacterial TCA cycle. Collectively, the synergistic antibacterial treatments of SDT, CDT, and cuproptosis‐like death via Cu 2 O/CD can realize the thorough sterilization and biofilm elimination. The work presents a novel perspective on how to optimize the function and safety of cuproptosis inducers, ultimately maximizing therapeutic advantages while minimizing harm to normal tissues.