Although Fe@Au nanoparticles show a similar cancer-preferential cytotoxicity in colorectal cancers (CRC), it seems that CRC is much more resistant to Fe@Au treatment, compared with oral cancer cells.17 However, the underlying mechanism of CRC resistance to the Fe@Au treatment is still unclear. Unraveling the puzzle of differential responses of different cancer types to Fe@Au treatment should lead to more efficient anticancer strategies in the future. Therefore, the research presented here aims to investigate the differential response of CRC to Fe@Au treatment. We first investigated the underlying molecular mechanisms of the cytotoxicity induced by Fe@Au in CRC and then explored the role of different elements in anticancer properties that we observed.