Three Birds with One Stone: Copper Ions Assisted Synergistic Cuproptosis/Chemodynamic/Photothermal Therapy by a Three‐Pronged Approach

Copper is indispensable to organisms, while its homeostatic imbalance may interference normal cellular physiological processes and even induce cell death. Artificially regulating cellular copper content provides a viable strategy to activate antineoplastic effect. In light of this, a copper ions homeostasis perturbator (CuP‐CL) with cinnamaldehyde (Cin) packaging and thermosensitive liposome coating is reported. Following laser exposure, the doping of Cu2+ in polydopamine initiates enhanced photothermal therapy (PTT) and unlocks the outer layer of liposome, leading to the release of copper ions and Cin in tumor microenvironment with mild acidity and high glutathione (GSH) levels. The liberative Cu2+ can evoke cuproptosis and chemodynamic therapy (CDT). Meanwhile, leveraging the merits of H2O2 supply and GSH consumption, Cin serves as a tumor microenvironment regulator to amplify Cu2+ mediated cuproptosis and CDT. Additionally, the positive feedback effects of “laser‐triggered PTT, PTT accelerates reactive oxygen species (ROS) generation, ROS amplifies lipid peroxide (LPO) accumulation, LPO mediates heat shock proteins (HSPs) clearance, down‐regulated HSPs promote PTT” entailed the overall benefit to therapeutic outcomes. Both in vitro and in vivo results corroborate the remarkable antineoplastic performance of CuP‐CL by the synergy of cuproptosis/CDT/PTT. Collectively, based on the three‐pronged approach, this work plots a viable multimodal regimen for cancer therapy. Owing to the doping of copper ions, the synthesized CuP‐CL enables enhanced photothermal therapy (PTT), which further unlocks copper ions mediated/cinnamaldehyde promoted cuproptosis and chemodynamic therapy (CDT). Additionally, there are positive feedback effects between PTT and CDT. Overall, this work provides a promising strategy for liver cancer therapy by a three‐pronged approach mediated by copper ions.