Fe/Cu Bimetallic Nanozyme Co‐Assembled with 177Lu and Tanshinone for Quadruple‐Synergistic Tumor‐Specific Therapy

Abstract The co‐loading of radionuclides and small‐molecule chemotherapeutic drugs as nanotheranostic platforms using nanozymes holds tremendous potential for imaging‐guided synergistic therapy. This study presents such nanotheranostic platform ( 177 Lu‐MFeCu@Tan) via co‐assembling 177 Lu radionuclide and tanshinone (Tan) into Fe/Cu dual‐metal nanozyme (MFeCu). This platform simultaneously enables single‐photon emission computed tomography (SPECT) imaging and a quadruple‐synergistic tumor therapy approach, including internal radioisotope therapy (RIT), catalysis therapy, chemotherapy, and MFeCu‐mediated ferroptosis and cuproptosis therapy. In this platform, the MFeCu can catalyze excessive intracellular hydrogen peroxide (H 2 O 2 ) to generate radical oxygen species (ROS) and deplete glutathione (GSH). The excess of H 2 O 2 and GSH are main factors for radioresistance and chemoresistance, reducing them can enhance chemotherapy and RIT. The generated ROS and depleted GSH further induce mitochondrial dysfunction and promote the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase and lipid peroxidation, causing the enhance of ferroptosis and cuproptosis. The in vitro and in vivo results demonstrate that this quadruple‐synergistic approach shows significant therapeutic efficacy to complete tumor eradication and reduced recurrence in vivo. In conclusion, this work presents a promising strategy for designing SPECT imaging‐guided quadruple‐synergistic therapy and highlights the feasibility of developing a self‐assembled radionuclide and small molecule chemotherapy drugs nanotherapeutic platform for combined treatment of cancer.