Specific “Unlocking” Nanozyme‐based Butterfly Effect for Breaking the Evolutionary Fitness of Chaotic Tumor

Chaos and natural evolution of tumor system have become two reasons of the failure of tumor therapies. Selectively targeting chaotic tumor systems to induce a "butterfly effect" is promising in constructing non-interventional and effective strategy for tumor therapy. Herein, we demonstrate for the first time that iridium oxide nanoparticles (IrO x ) possess acid-activated oxidase and peroxidase-like functions and wide pH-dependent catalase-like properties. Integrating of glucose oxidase (GOD) could unlock its oxidase and peroxidase activities by gluconic acid produced by catalysis of GOD towards glucose in cancer cells, and the produced H 2 O 2 can be converted to O 2 to compensate its consumption in GOD catalysis due to the catalase-like function of the nanozyme, which result in continual consumption of glucose and self-supplied substrates for generating superoxide anion and hydroxyl radical. Moreover, IrO x can constantly consume glutathione (GSH) by self-cyclic valence alteration of Ir (IV) and Ir (III), greatly reducing the anti-oxidation defense effect of tumor. Consequently, these self-cyclic parallel cascaded reactions due to the introduction of IrO x -GOD into chaotic tumor lead to a "butterfly effect" of initial starvation therapy and subsequent multiple reactive oxygen species (ROS) pressure, completely break the self-adaption of cancer cells compared to traditional ROS- and GSH- targeted therapies, providing new conceptual thinkings for non-interventional and precise cancer therapy against the resistance.