Suppression of Energy Metabolism in Cancer Cells with Nutrient-Sensing Nanodrugs

Uncontrolled growth of tumor cells is highly dependent on the energy metabolism. Fasting-mimicking diet (FMD) is a low-calorie, low-protein, low-sugar diet representing a promising strategy for cancer treatment. However, triglyceride stored in adipose tissue is hydrolyzed into free fatty acids and glycerol for energy supply during FMD treatment. Herein, we design a nutrient-sensing nanodrug, VFETX, which is self-assembled with vitamin B1 (VB1), ferrous ions, and etomoxir (ETX). FMD treatment upregulate the expression of VB1 transporters on tumor cells, thereby increasing cellular uptake and tumor accumulation of VFETX. Importantly, treatments of VFETX and FMD synergistically inhibit the energy metabolism in tumor cells and subsequently markedly enhance cytotoxicity of ETX. As a result, VFETX nanodrugs efficiently inhibit the growth of two tumor models in vivo without obvious side effects. This study demonstrates the potential of FMD-assisted nutrient-sensing nanodrugs for cancer therapy.