In recent years, the growing application of metal oxide nanoparticles in medicine, industry and consumer products has led to an increase in human exposure to these materials (whether intentional or unintentional). On the other hand, oxidative stress is one of the key axes in the pathophysiology of Alzheimer’s disease and other neurodegenerative disorders, and changes in the activity/structure of antioxidant enzymes can play a reinforcing role in this cycle. Authoritative reviews have shown that oxidative stress is intertwined with metabolic disorders, neuroinflammation and protein/lipid damage in Alzheimer’s. In this study, magnetic iron oxide nanoparticles (MONPs), copper oxide (CuO NPs) and zinc oxide (ZnO NPs) were synthesized and then their interaction with the enzyme superoxide dismutase (SOD) was investigated in a statistical design (CCD). A colorimetric kit based on the production of superoxide by xanthine oxidase and the reduction of tetrazolium salt to formazan (reading around 450 nm) was used to measure SOD activity. In addition to activity, the physicochemical changes of nanoparticles as well as the structural changes of SOD after interaction were evaluated by DLS/zeta, UV-Vis, SEM, XRD, CD and SDS-PAGE (to examine the protein crown and approximate separation of soft/hard crown). The results showed that the changes in SOD activity are not severe and destructive in most conditions, but the type of nanoparticle and the contact time/ratio can create different patterns in protein structure and nanoparticle aggregation behavior; the corona phenomenon is also visible/confirmed as a new biological identity of the nanoparticle.