Metabolic intervention mitochondria nanomotors breakdown redox homeostasis for boosting oxidative stress-dependent antitumor therapy

Abstract

Aberrant metabolic balance in malignant tumors shapes defensive redox homeostasis and protected tumor cells from oxidative stress damage, consequently impeding clinical transformation process of oxidative stress-dependent anti-tumor therapies represented by chemodynamic therapy and immunotherapy. Herein, a rational designed mitochondria nanomotor was developed by coating a GSH-responsive functional Pt(IV) prodrug layer DP on magnetic iron oxide nanoparticles (MN), which can thoroughly breakdown redox homeostasis by metabolic intervention strategy. Specifically, DP loading two dichloroacetic acid (DCA) axial ligands was stimuli-responsively reduced into Pt(II) and DCA molecules in highly reductive tumor cells, accompanied with glutathione elimination and oxidative stress counteraction weakening. Subsequently, DCA increased pyruvate influx into the mitochondria by pyruvate dehydrogenase activation and enduringly elevated oxidative phosphorylation level, breaking the tumor redox homeostasis thoroughly, contributing to 7.5-fold amplifying hydrogen peroxide production and sensitizing chemodynamic therapy mediated by MN, finally resulting in inspiring 89.5% tumor suppression rate on triple negative breast cancer model. In short, this work realized comprehensive and sustainable oxidative stress elevation of the intracellular environment by metabolic intervention strategy and provided an ingenious perspective of augmenting oxidative stress-dependent anti-tumor therapies.