Enhanced Tumor Synergistic Therapy by Injectable Magnetic Hydrogel Mediated Generation of Hyperthermia and Highly Toxic Reactive Oxygen Species

Abstract Nanoparticle-mediated tumor magnetic induction hyperthermia has received tremendous attention. However, it has been a challenge to improve the efficacy at 42 °C therapeutic temperatures without resistance to induced thermal stress. Therefore, we designed a magnetic hydrogel nanozyme (MHZ) utilizing inclusion complexation between PEGylated nanoparticles and α-cyclodextrin, which can enhance tumor oxidative stress levels by generating reactive oxygen species through nanozyme-catalyzed reactions based on tumor magnetic hyperthermia. MHZ can be injected and diffused into the tumor tissue due to shear thinning as well as magnetocaloric phase transition properties, and magnetic heat generated by the Fe3O4 first gives 42 °C of hyperthermia to the tumor. Fe3O4 nanozyme exerts peroxidase-like properties in the acidic environment of tumor to generate hydroxyl radicals (•OH) by the Fenton reaction. The hyperthermia promotes the enzymatic activity of Fe3O4 nanozyme to produce more •OH. Simultaneously, •OH further damages the protective heat shock protein 70, which is highly expressed in hyperthermia to enhance the therapeutic effect of hyperthermia. This single magnetic nanoparticle exerts dual functions of hyperthermia and catalytic therapy to synergistically treat tumors, overcoming the resistance of tumor cells to induced thermal stress without causing severe side effects to normal tissues at 42 °C hyperthermia.