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

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.