Ultrasound and ROS-responsive nanodroplets inhibit TCA cycle in hepatocellular carcinoma

Abnormal energy metabolism patterns are common characteristics of various tumor cells, including hepatocellular carcinoma cells (HCC). HCC undergo metabolic reprogramming, upregulating the tricarboxylic acid (TCA) cycle and mitochondrial respiration to provide energy. Based on this, we constructed a novel reactive oxygen species (ROS)- and ultrasound-responsive nanodroplet (named sGTND), which were loaded with glucose-6-phosphate dehydrogenase (G6PD) siRNA and modified with glycyrrhetinic acid (GA) via GTC polymer. These sGTNDs have a particle size of approximately 300 nm, exhibit excellent biocompatibility and contrast-enhanced ultrasound imaging. By recognizing GA receptors, sGTNDs can be specifically targeted and enriched within HCC. Under the combined effect of ultrasound-targeted microbubble destruction (UTMD), sGTNDs release GA to activate the nuclear factor erythroid 2-related factor 2 (NRF2) while simultaneously releasing siRNA to inhibit G6PD. This dual action synergistically inhibits the TCA cycle, resulting in an antitumor efficacy of up to 95.1%, which is significantly higher than that observed in the control groups. Thus, the combination of sGTND and UTMD can effectively inhibit the TCA cycle through NRF2 activation and G6PD inhibition, which represents a promising therapeutic approach for HCC.