Shikonin-Cu(II) Supramolecular Polymers Exhibit Antitumor Activity via Necrosis and Cuproptosis.

Supramolecular polymers driven by the metal-ligand coordination possess reversible bonds, making them promising candidates for integrating the therapeutic functions of metal ions and small-molecule drugs, and subsequently releasing these components within cells after endocytosis. In this study, a kind of supramolecular polymer, SHICU, is developed, composed of Shikonin ligand and Cu(II) ion. Upon reduction by intracellular glutathione (GSH), SHICU dissociates to release Shikonin, Cu(II), and SHICU fragments. The released Shikonin and Cu(II) exhibit a synergistic antitumor effect through the reactive oxygen species (ROS)-dependent necrosis. Meanwhile, the released SHICU that remains structural integrity induces a distinct antitumor mechanism by triggering cuproptosis in tumor cells. This dual functionality, combining ROS-dependent necrosis and cuproptosis, highlights the potential of SHICU in advancing antitumor therapies, while the integration of supramolecular polymers with the emerging cell death mechanism of cuproptosis facilitates the development of innovative cancer drugs.