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, two-dimensional (2D) WS 2 nanosheets were prepared and functionalized with mitochondrial-targeting triphenylphosphonium (TPP) for ultrasound (US)-triggered, mitochondria-targeted piezodynamic cancer therapy. In addition, a glycolysis inhibitor (FX11) that can inhibit cellular energy metabolism was loaded into TPP- and poly(ethylene glycol) (PEG)-conjugated WS 2 nanosheets (TPEG-WS 2 ) to potentiate its piezodynamic therapeutic efficacy. FX11-loaded TPEG-WS 2 (FX11@TPEG-WS 2 ) exhibited high physiological stability and biocompatibility. Upon US irradiation, the sono-excited electrons and holes generated in the 2D WS 2 were efficiently separated by piezoelectric polarization, which subsequently promoted the production of ROS. The variation in the piezoelectric potential with respect to US-induced pressure was calculated using COMSOL Multiphysics®. TPEG-WS 2 selectively accumulates in the mitochondria of human breast cancer cells, rendering them more vulnerable to ROS-triggered apoptosis. In addition, FX11@TPEG-WS 2 effectively inhibited glycolytic pathways, leading to the significant inhibition of adenosine triphosphate and lactate production. Thus, FX11@TPEG-WS 2 exhibited outstanding anticancer effects under US irradiation. An in vivo biodistribution study using tumor-xenograft mice demonstrated that FX11@TPEG-WS 2 effectively accumulated in the tumors. Tumor accumulation of FX11@TPEG-WS 2 was also visualized using in vivo computed tomography imaging. Notably, a single intravenous injection of FX11@TPEG-WS 2 under US irradiation remarkably suppressed the tumor growth of mice without systemic toxicity. This study demonstrates that the combination of US-triggered piezodynamic cancer therapy and energy metabolism-targeted chemotherapy using mitochondria-targeting piezoelectric 2D WS 2 nanosheets is a novel therapeutic strategy for the selective and effective treatment of tumors . This article is protected by copyright. All rights reserved.