A copper-based nanotherapeutic overcomes multidrug- resistant breast cancer by blocking drug efflux and triggering cuproptosis.

Multidrug-resistance (MDR) remains a formidable obstacle in the treatment of breast cancer, primarily due to the overexpression of P-glycoprotein (P-gp) efflux pumps. The objective of this study is to develop a copper-based nanotherapeutic agent capable of simultaneously inhibiting drug efflux and inducing a novel form of cell death, cuproptosis, to overcome MDR. The nanoparticle known as DOX-P-gp ASO-Cu2 + NPs has been engineered to facilitate the delivery of doxorubicin (Dox), P-gp antisense oligonucleotide (P-gp ASO), and copper ions into cancer cells. The incorporation of ASO effectively silenced P-gp expression, significantly enhancing the retention of Dox within the cells. Consequently, the IC50 value of Dox in the nanoparticle formulation was reduced by 17.5-fold compared to free Dox in MCF-7/ADM cells. This synergistic strategy not only restored chemosensitivity but also triggered cuproptosis, as evidenced by mitochondrial dysfunction, downregulation of LIAS/FDX1, and DLAT oligomerization. The results of drug-resistant breast cancer xenograft model further demonstrated superior tumor suppression with the nanoformulation compared to monotherapy. This integrated strategy, which involves the inhibition of drug efflux and the induction of cuproptosis, offers a promising approach to eradicating multidrug-resistant breast cancer.