Single‐Atom Cu Nanozyme‐Loaded Bone Scaffolds for Ferroptosis‐Synergized Mild Photothermal Therapy in Osteosarcoma Treatment

Abstract The rapid multiplication of residual tumor cells and poor reconstruction quality of new bone are considered the major challenges in the postoperative treatment of osteosarcoma. It is a promising candidate for composite bone scaffold which combines photothermal therapy (PTT) and bone regeneration induction for the local treatment of osteosarcoma. However, it is inevitable to damage the normal tissues around the tumor due to the hyperthermia of PTT, while mild heat therapy shows a limited effect on antitumor treatment as the damage can be easily repaired by stress‐induced heat shock proteins (HSP). This study reports a new type of single‐atom Cu nanozyme‐loaded bone scaffolds, which exhibit exceptional photothermal conversion properties as well as peroxidase and glutathione oxidase mimicking activities in vitro experiments. This leads to lipid peroxidation (LPO) and reactive oxygen species (ROS) upregulation, ultimately causing ferroptosis. The accumulation of LPO and ROS also contributes to HSP70 inactivation, maximizing PTT efficiency against tumors at an appropriate therapeutic temperature and minimizing the damage to surrounding normal tissues. Further, the bone scaffold promotes bone regeneration via a continuous release of bioactive ions (Ca 2+ , P 5+ , Si 4+ , and Cu 2+ ). The results of in vivo experiments reveal that scaffolds inhibit tumor growth and promote bone repair.