Ultrasound-activated metal-polyphenol nanodroplets for tumor cuproptosis

Cuproptosis is a novel form of cell death that relies on mitochondrial metabolism and has opened up new avenues for tumor therapy. However, resistance to cuproptosis in tumors can arise from several factors, such as their reliance on aerobic glycolysis, the high-glutathione (GSH) environment, and inefficient copper (Cu) delivery. In this study, we developed shell-core nanodroplets (NDs) approximately 280 nm in diameter, named Cu-EGCG-SHK-NDs. These NDs are composed of a liquid-gas phase-change perfluorohexane core and a carboxymethyl chitosan shell, loaded with the glycolytic inhibitor shikonin (SHK) and coated with Cu-complexed epigallocatechin gallate (Cu-EGCG), enabling targeted delivery through ultrasound (US)-targeted microbubble destruction (UTMD). The dual responsiveness of NDs to both US and pH enables precise drug release and efficient intracellular uptake. In addition, the US response enhances contrast-enhanced US imaging and triggers the generation of reactive oxygen species, subsequently depleting GSH. Both in vitro and in vivo experiments confirm that Cu-EGCG-SHK-NDs possess excellent biocompatibility. Combined with UTMD, they can efficiently co-deliver Cu and SHK into tumour cells, inhibit glycolytic metabolism, and significantly reduce intracellular GSH levels. This synergistic mechanism enhances cuproptosis induction and achieves effective tumour growth inhibition.