Cycloacceleration of Reactive Oxygen Species Generation Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for Tumor Ferroptosis Therapy

Abstract Because of the insufficiency of hydrogen peroxide, the relatively low rate of Fenton reaction, and the active glutathione (GSH) peroxidase 4 (GPX4) in tumor cells, it is difficult to achieve a desirable efficacy of ferroptosis therapy (FT) for tumors based on nanomaterials. Inspired by the concept of “cyclotron” in physics, in this study, a new concept of cycloacceleration of reactive oxygen species (ROS) generation in tumor cells to realize high‐performance FT of tumors is proposed. Typically, a magnetic resonance imaging (MRI) contrast agent of dotted core–shell Fe 3 O 4 /Gd 2 O 3 hybrid nanoparticles (FGNPs) is prepared based on exceedingly small magnetic iron oxide nanoparticles (ES‐MIONs). Sorafenib (SFN) is loaded and poly(ethylene glycol) methyl ether‐poly(propylene sulfide)‐NH 2 (mPEG‐PPS‐NH 2 ) is grafted on the surface of FGNP to generate SA‐SFN‐FGNP via self‐assembly. The results of in vitro and in vivo demonstrate SA‐SFN‐FGNP can work with the acidic tumor microenvironment and endosomal conditions, Fenton reaction and system X C − , and generate cyclic reactions in tumor cells, resulting in specific cycloacceleration of ROS generation for high‐performance FT of tumors. The very high longitudinal relaxivity ( r 1 , 33.43 mM −1 s −1 , 3.0 T) makes sure that the SA‐SFN‐FGNP can be used for MRI‐guided FT of tumors.