Piezoelectric Catalysis‐Induced Intratumoral Carbon Monoxide Explosion for Tumor Respiration Inhibition

Abstract Carbon monoxide (CO) demonstrates significant potential in cancer therapy due to its potent cytotoxicity and excellent tissue permeability. However, conventional CO delivery strategies, which often rely on nanocarriers to transport CO to tumor sites, are frequently associated with leakage into healthy tissues, leading to severe toxic side effects. This study proposes a novel therapeutic modality that initiates localized piezoelectric catalysis to generate CO within tumors, inducing cancer cell apoptosis by specifically disrupting mitochondrial respiration. A Cu‐based metal‐organic framework (Cu‐MOF) is designed as the piezoelectric catalyst, and a layer of CaCO 3 is mineralized on its surface to construct the final nanomedicine Cu‐MOF@CaCO 3 . Following passive accumulation in tumor tissue, the acidic tumor microenvironment triggers the decomposition of CaCO 3 into CO 2 . Subsequently, under ultrasound (US) activation, the Cu‐MOF converts the biologically inert CO 2 into cytotoxic CO directly by piezoelectric catalysis. This locally generated CO selectively impairs mitochondrial function in cancer cells, suppressing cellular respiration and ultimately triggering cell apoptosis. The results demonstrate that the piezoelectric catalysis‐based CO therapy can produce 155.3 µM CO within tumor cells, which disrupts mitochondrial function, and achieves a remarkable tumor inhibition rate of 93.8% in vivo.