Copper‐Based Nanodrug for Enhancing Inhibitory Effect of Doxorubicin on Drug‐Resistant Breast Cancer Cells by Multiple Pathways

Breast cancer is one of the most common malignancies. Despite the continuous advancement in therapeutic approaches, the emergence of multidrug resistance (MDR) in cancer cells against chemotherapeutic agents such as doxorubicin (DOX) has posed significant challenges to cancer treatment, highlighting an urgent need for the development of novel therapeutic strategies. Studies have demonstrated that the antisense oligonucleotide MB1 and microRNA MiR489 can inhibit the expression of P‐glycoprotein and Smad3, respectively, which are associated with tumor MDR. Additionally, Cu ²⁺ can disrupt cellular metabolism, trigger proteotoxic stress responses, and induce cuproptosis in cells. Therefore, in this study, functional nucleic acids (MB1 and miR489), Cu ²⁺ , and DOX were assembled into an integrated novel nanodrug system DOX/Cu ²⁺ @(MB1+MiR489). This system enables the delivery of membrane‐impermeable functional nucleic acids into cells without the need for additional carriers, thereby enhancing the inhibitory effect of DOX on drug‐resistant breast cancer cells. The results showed that DOX/Cu ²⁺ @(MB1+MiR489) reduced the IC ₅₀ of DOX against MCF‐7/ADM cells by 18‐fold, significantly alleviated the resistance of drug‐resistant breast cancer cells to DOX, and markedly inhibited their proliferation and migration.