# A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells

## TL;DR

This study introduces a new copper ionophore, Cu(HEDTC)2, that effectively induces cuproptosis in melanoma cells, offering a potential new cancer treatment strategy.

## Contribution

The development of Cu(HEDTC)2@Soluplus-nanomicelle system as a novel copper ionophore for enhancing cuproptosis in melanoma cells.

## Key findings

- Cu(HEDTC)2 shows superior intracellular copper delivery compared to traditional ionophores.
- The CS NM system disrupts copper homeostasis and triggers cuproptosis via mitochondrial protein aggregation.

## Abstract

Cuproptosis, a newly discovered copper-dependent programmed cell death pathway, represents a promising approach for anticancer therapy. However, the efficacy of cuproptosis critically depends on intracellular copper accumulation. Traditional copper ionophores have limited therapeutic efficacy due to their reliance on serum copper levels. Therefore, the development of novel copper ionophores to enhance intracellular copper levels is urgently needed. In this study, we targeted a melanoma model and pioneered the application of Bis(2-hydroxyethyl)dithiocarbamic acid copper(II) [Cu(HEDTC)2] as a highly efficient copper ionophore for inducing cuproptosis in B16 melanoma cells. Compared to conventional copper ionophores, Cu(HEDTC)2 exhibits superior intracellular copper delivery efficiency, thereby enhancing the induction of cuproptosis. We further constructed a Cu(HEDTC)2@Soluplus-nanomicelle (CS NM) system designed to disrupt copper ion homeostasis in tumor cells and amplify cuproptosis. In this system, Cu(HEDTC)2, as a novel copper ionophore, significantly enhanced the copper level in B16 melanoma cells. Upon cellular internalization, CS NM underwent degradation and released copper ions, which subsequently triggered cuproptosis by causing abnormal aggregation of mitochondrial lipoylated proteins. This study provides a new experimental foundation and potential therapeutic strategy for cuproptosis-based cancer treatment.