An Ellagic Acid Coordinated Copper‐Based Nanoplatform for Efficiently Overcoming Cancer Chemoresistance by Cuproptosis and Synergistic Inhibition of Cancer Cell Stemness

Drug resistance is one of the leading causes of treatment failure in current cancer chemotherapy. In addition to the classical drug efflux transporter-mediated chemoresistance, cancer cells with stemness features play a crucial role in escaping the maximum impact of chemotherapy. To sensitize cancer chemotherapy, in a novel approach, the hedgehog pathway inhibitor ellagic acid (EA) is coordinated with Cu2+ to develop nanoscale metal-organic frameworks (EA-Cu), which are then loaded with doxorubicin (DOX) and modified with targeted chondroitin sulfate (CS) to form the CS/E-C@DOX nanoplatform (CS/NPs). Notably, EA inhibits stemness maintenance by suppressing the hedgehog pathway, while Cu2+ further decreases stemness features of tumor cells by disrupting mitochondrial metabolism, effectively enhancing DOX-mediated chemotherapy. Meanwhile, EA can act synergistically with Cu2+ to cause mitochondrial dysfunction and cuproptosis, which effectively decreases ATP levels and subsequently suppresses the activity of P-glycoprotein (P-gp), thus reducing drug efflux and sensitizing DOX-mediated chemotherapy. Additionally, the attached CS endows CS/NPs with specific tumor targeting properties, whereas EA-Cu endows this nanoplatform with pH/glutathione (GSH) dual-responsive release behavior. Taken together, CS/NPs exhibited excellent antitumor effects by inducing cuproptosis and significantly inhibiting cancer cell stemness, which has great potential for overcoming cancer chemoresistance.