Sheng Tong

Iron oxide nanoparticles (IONPs) have garnered significant attention as a promising platform for reactive oxygen species (ROS)‐dependent disease treatment, owing to their remarkable biocompatibility and Fenton catalytic activity. However, the low catalytic activity of IONPs is a major hurdle in their clinical translation. To overcome this challenge, IONPs of different compositions are examined for their Fenton reaction under pharmacologically relevant conditions. The results show that wüstite (FeO) nanoparticles exhibit higher catalytic activity than magnetite (Fe 3 O 4 ) or maghemite (γ‐Fe 2 O 3 ) of matched size and coating, despite having a similar surface oxidation state. Further analyses suggest that the high catalytic activity of wüstite nanoparticles can be attributed to the presence of internal low‐valence iron (Fe 0 and Fe 2+ ), which accelerates the recycling of surface Fe 3+ to Fe 2+ through intraparticle electron transport. Additionally, ultrasmall wüstite nanoparticles are generated by tuning the thermodecomposition‐based nanocrystal synthesis, resulting in a Fenton reaction rate 5.3 times higher than that of ferumoxytol, an FDA‐approved IONP. Compared with ferumoxytol, wüstite nanoparticles substantially increase the level of intracellular ROS in mouse mammary carcinoma cells. This study presents a novel mechanism and pivotal improvement for the development of highly efficient ROS‐inducing nanozymes, thereby expanding the horizons for their therapeutic applications.