Cepharanthine Loaded TCPP‐MOF Triggers Pyroptosis Through TSPO Inhibition for Hepatocellular Carcinoma Sonodynamic‐Chemotherapy

Abstract Pyroptosis is the critical approach for the induction of robust cancer cell death and activation of the immune microenvironment, which often results from mitochondrial damage. Herein, a combination strategy of sonodynamic‐chemotherapy is designed to achieve an anti‐heptocellular (HCC) effect, wherein the cepharanthine (Cep), a kind of functional phytomedicine, is loaded into the Tris(chlorisopropyl)Phosphate (TCPP) Metal–organic framework (MOF). The Cep@TCPP‐MOF is successfully developed, as characterized by techniques such as transmission electron microscopy (TEM) and dynamic light scattering (DLC). The tumor‐targeted ability of Cep@TCPP‐MOF is validated by in vivo imaging. In‐depth in vitro experiments presented Cep@TCPP‐MOF can be taken up by Huh‐7 and HepG2 cells, which collapse in response to the sonodynamic therapy (SDT). The released Cep can bind to an inactive translocator protein (TSPO), a kind of transporter on the membrane of mitochondria, while TCPP induces ROS generation under the SDT, thereby enhancing mitochondria damage. Further exploration shows that the Cep@TCPP‐MOF treatment induces pronounced pyroptosis, which leads to HCC inhibition. To sum up, sonodynamic‐chemotherapy nanoplatforms, composed by Cep‐loaded TCPP‐MOF are developed, which have sonodynamic responsiveness to release Cep and TCPP. TSPO inhibition‐induced mitochondrial damage by Cep, coupled with ROS generated by TCPP‐SDT, synergistically elicits pyroptosis and thereby fulfills the anti‐HCC role.