Copper-coordinated nanomedicine for the concurrent treatment of lung cancer through the induction of cuproptosis and apoptosis

The resistance of tumor cells to apoptosis often leads to chemoresistance and treatment failure in clinic. In this study, we have developed a Cu²⁺-coordinated lignosulfonate (CLS) /doxorubicin (DOX) biological complex (referred to as LCD) with the aim of overcoming cellular resistance to apoptosis for combined lung cancer therapy. The copper complexes modified by CLS exhibit significant water solubility and excellent in vivo biocompatibility. The proportion of copper in the composite is simultaneously increased. Due to the coordination and π-π stacking effects, the self-assembled LCD exhibits nanometer-scale particle size, a narrow and homogeneous grain distribution, as well as excellent dispersion stability. Furthermore, LCD has the potential to disassemble in the presence of high levels of glutathione (GSH) and low pH, leading to effective drug release. Cu²⁺-mediated cuproptosis can lead to the down-regulation of FDX1 and DLAT protein expression by reducing mitochondrial membrane potential, resulting in non-apoptotic programmed cell death (PCD) regardless of cellular resistance to apoptosis. Moreover, the released DOX not only exhibits a preference for localizing in the cell nucleus to induce apoptosis for combined chemotherapy, but also generates a substantial amount of H₂O₂. This H₂O₂ further produces ROS to induce apoptosis through Fenton reaction with Cu²⁺. LCD demonstrates significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity through the combined action of cuproptosis and apoptosis. This study may provide a potential avenue for the advancement of self-delivery nanomedicine to overcome resistance to apoptosis in tumor therapy.