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

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 Cu2 + 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.