Piezocatalytic 2D WS2 Nanosheets for Ultrasound‐Triggered and Mitochondria‐Targeted Piezodynamic Cancer Therapy Synergized with Energy Metabolism‐Targeted Chemotherapy

Abstract Piezoelectric nanomaterials that can generate reactive oxygen species (ROS) by piezoelectric polarization under an external mechanical force have emerged as an effective platform for cancer therapy. In this study, piezoelectric 2D WS 2 nanosheets are functionalized with mitochondria‐targeting triphenylphosphonium (TPP) for ultrasound (US)‐triggered, mitochondria‐targeted piezodynamic cancer therapy. In addition, a glycolysis inhibitor (FX11) that can inhibit cellular energy metabolism is loaded into TPP‐ and poly(ethylene glycol) (PEG)‐conjugated WS 2 nanosheet (TPEG‐WS 2 ) to potentiate its therapeutic efficacy. Upon US irradiation, the sono‐excited electrons and holes generated in the WS 2 are efficiently separated by piezoelectric polarization, which subsequently promotes the production of ROS. FX11‐loaded TPEG‐WS 2 (FX11@TPEG‐WS 2 ) selectively accumulates in the mitochondria of human breast cancer cells. In addition, FX11@TPEG‐WS 2 effectively inhibits the production of adenosine triphosphate . Thus, FX11@TPEG‐WS 2 exhibits outstanding anticancer effects under US irradiation. An in vivo study using tumor‐xenograft mice demonstrates that FX11@TPEG‐WS 2 effectively accumulated in the tumors. Its tumor accumulation is visualized using in vivo computed tomography . Notably, FX11@TPEG‐WS 2 with US irradiation remarkably suppresses the tumor growth of mice without systemic toxicity. This study demonstrates that the combination of piezodynamic therapy and energy metabolism‐targeted chemotherapy using mitochondria‐targeting 2D WS 2 is a novel strategy for the selective and effective treatment of tumors.