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

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 WS₂ 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 WS₂ nanosheet (TPEG-WS₂) to potentiate its therapeutic efficacy. Upon US irradiation, the sono-excited electrons and holes generated in the WS₂ are efficiently separated by piezoelectric polarization, which subsequently promotes the production of ROS. FX11-loaded TPEG-WS₂ (FX11@TPEG-WS₂) selectively accumulates in the mitochondria of human breast cancer cells. In addition, FX11@TPEG-WS₂ effectively inhibits the production of adenosine triphosphate. Thus, FX11@TPEG-WS₂ exhibits outstanding anticancer effects under US irradiation. An in vivo study using tumor-xenograft mice demonstrates that FX11@TPEG-WS₂ effectively accumulated in the tumors. Its tumor accumulation is visualized using in vivo computed tomography. Notably, FX11@TPEG-WS₂ 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 WS₂ is a novel strategy for the selective and effective treatment of tumors.