In situ hydrogel based on Cu–Fe3O4 nanoclusters exploits oxidative stress and the ferroptosis/cuproptosis pathway for chemodynamic therapy

Chemodynamic therapy (CDT) involving the use of metal nanozymes presents new opportunities for the treatment of deep-seated tumors. However, the lower ROS catalytic rate and dependence on high H₂O₂ concentrations affect therapeutic efficacy. To address this issue, a hydrogel was constructed for the treatment of osteosarcoma by combining Cu–Fe₃O₄ nanozymes (NCs) and artemisinin (AS) coencapsulated in situ with sodium alginate (ALG) and calcium ions. This hydrogel can release nanoparticles and AS within tumor tissue for an extended period of time, utilizing the multienzyme activity of NCs to achieve ROS accumulation. The carbon radicals (•C) generated from the interaction of Fe²⁺/Cu²⁺ with AS amplify oxidative stress, leading to tumor cell damage. Simultaneously, the NCs activate ferroptosis via the GPX4 pathway by depleting GSH and activate cuproptosis via the DLAT pathway by causing intracellular copper overload, enhancing therapeutic efficacy. In vitro experiments confirmed that the NCs-AS-ALG hydrogel has an excellent tumor cell killing effect, while in vivo experimental results demonstrated that it can effectively eliminate tumors with excellent biocompatibility, providing a new approach for osteosarcoma treatment.