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Simple Summary: Image-guided stereotactic body radiation therapy (SBRT), utilizing biocompatible superparamagnetic iron oxide nanoparticles (SPION), like ferumoxytol, has emerged as a non-invasive, safe, and effective therapy for liver tumors. However, the radiomodulating properties of ferumoxytol on hepatic macrophages have never been directly investigated. We showed that ferumoxytol affected human monocytes increasing their resistance to radiation-induced cell death. These findings provide the basis for mechanism-based optimization of SPION-enhanced image-guided functional treatment planning platform for reducing hepatotoxicity in patients with advanced hepatic cirrhosis undergoing liver SBRT for liver cancer before liver transplant. Superparamagnetic iron oxide nanoparticles (SPION) have attracted great attention not only for therapeutic applications but also as an alternative magnetic resonance imaging (MRI) contrast agent that helps visualize liver tumors during MRI-guided stereotactic body radiotherapy (SBRT). SPION can provide functional imaging of liver parenchyma based upon its uptake by the hepatic resident macrophages or Kupffer cells with a relative enhancement of malignant tumors that lack Kupffer cells. However, the radiomodulating properties of SPION on liver macrophages are not known. Utilizing human monocytic THP-1 undifferentiated and differentiated cells, we characterized the effect of ferumoxytol (Feraheme®), a carbohydrate-coated ultrasmall SPION agent at clinically relevant concentration and therapeutically relevant doses of gamma radiation on cultured cells in vitro. We showed that ferumoxytol affected both monocytes and macrophages, increased the resistance of monocytes to radiation-induced cell death and inhibition of cell activity, and supported the anti-inflammatory phenotype of human macrophages under radiation. Its effect on human cells depended on the duration of SPION uptake and was radiation dose-dependent. The results of this pilot study support a strong mechanism-based optimization of SPION-enhanced MRI-guided liver SBRT for primary and metastatic liver tumors, especially in patients with liver cirrhosis awaiting a liver transplant. [ABSTRACT FROM AUTHOR]