Asymmetric Cu─N─Ru Bridgedsite Nanozyme‐Loaded Injectable Thermogel Boosts Cuproptosis‐Like Death for Multidrug‐Resistant Urinary Tract Infections

ABSTRACT Multidrug‐resistant urinary tract infections (MDR‐UTIs) remain one of the most challenging clinical infections globally owing to the paucity of effective therapeutic agents. Nanozymes‐triggered cuproptosis‐like bacterial death has emerged as a promising bactericidal strategy. However, its efficacy is compromised by insufficient catalytic sites and suboptimal synergy among active centers. Consequently, the development of nanozymes capable of efficiently inducing cuproptosis‐like death holds considerable potential for treating MDR‐UTIs. Herein, the Cu‐ZIF8‐Ru nanozyme was engineered that leverages an asymmetric heterobimetallic Cu─N─Ru bridged catalytic center to achieve efficient multienzyme activities and trigger cuproptosis‐like death in MDR‐UTIs. Theoretical simulations revealed that introducing Ru sites as secondary catalytic centers upshifts the Cu d‐band center, thereby lowering activation barriers and enhancing catalytic activity at the Cu─N─Ru active site. Cu‐ZIF8‐Ru nanozyme demonstrated strong bactericidal effects against MDR‐bacteria by promoting intracellular Cu 2 + accumulation and depleting cellular energy, ultimately leading to cuproptosis‐like death. A thermogel encapsulating Cu‐ZIF8‐Ru enabled intravesical in situ gelation and sustained release, providing durable bactericidal and anti‐inflammatory effects in both acute and recurrent MDR‐UTIs models with a favorable biosafety. In summary, Cu‐ZIF8‐Ru offers an efficient, controllable, and low‐toxicity intravesical bactericidal strategy that addresses key clinical demands in MDR‐UTIs management and holds substantial translational promise.