# Metal Nanozymes: New Horizons in Cellular Homeostasis Regulation
## 3 Mechanisms of Pro-Oxidative and Antioxidant Action of Nanozymes  
Reactive oxygen species (ROS) such as O2*-, *OH, and H2O2 are natural byproducts of cellular metabolism [28]. Low ROS levels can serve as important transmitters in cell signaling and participate in many signaling processes [29]. However, overexpression of ROS leads to many undesirable effects, such as oxidative damage to lipids, proteins, DNA, and other biological molecules. Moreover, ROS can induce caspase to activate cell apoptosis [30; 31; 32; 33; 34]. Therefore, ROS overexpression is associated with many pathological conditions such as neurodegeneration, cancer, diabetes, atherosclerosis, arthritis, and kidney disease [35], contributing to aging and death. Therefore, the regulation of ROS levels is of great importance in maintaining intracellular redox homeostasis. It is assumed that the cytotoxicity of nanoparticles results from oxidative stress induction. Its mechanisms are well known and described in the literature. Nanomaterials can generate and induce ROS production through various mechanisms. Radicals such as O2*-, *OH, SiO*, or TiO* may be present on the surface of the nanomaterial. These, in turn, can generate secondary ROS. The nanomaterial surface may also contain structural defects inducing the formation of reactive groups [36], as well as transition metals that can generate ROS by Fenton and Haber-Weiss type reactions [37]. In addition, environmental oxidants such as ozone, semiquinones, and NO can adsorb to the nanomaterial surface and enter cells through the so-called \"Trojan horse effect\" [37]. Nanomaterials may also indirectly enable the production of ROS by triggering cellular mechanisms. For example, damage to or activation of mitochondria can lead to the release of ROS produced by the mitochondrial electron transport chain [38], structural damage, activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-like enzyme activity, and via irreversible membrane potential loss in the mitochondria [39; 40]. The native NADPH oxidase can also be activated by nanomaterials, as shown for ZnO NP [41]. This membrane-bound enzyme is highly expressed in neutrophils and macrophages, where it induces the so-called oxygen burst, designed to kill invading microorganisms by producing ROS. Nanomaterials can activate inflammatory cells, inducing oxygen burst in the absence of pathogens [42]. Macrophage activation is a particularly important mechanism for ROS production by the so-called long aspect ratio nanomaterials, as long, thin, and biopersistent fibers can lead  
Figure 2: Studies of activities mimicking the enzymes of catalytic nanoparticles based on metals and their oxides gain popularity. The graph denotes the number of publications on ‘metal nanozymes’ and ‘metal nanozymes medicine’ cited in Google Scholar by year. to 'frustrated phagocytosis' [43]. This mechanism led to the sustained release of oxidants and proinflammatory mediators and was first described as explaining the toxicity of asbestos but has since also been observed in carbon nanotubes (CNTs) [44]. The involvement of NADPH oxidase in the toxicity of CeO\({}_{2}\) and CoCr NP has also been demonstrated, for example, in fibroblasts [45]. Nanomaterials can also inhibit repair mechanisms that eliminate ROS-damaged molecules, enhancing their toxicity [46; 47]. Another indirect mechanism by which nanomaterials induce oxidative stress is depletion or inhibition of antioxidants, leading to an imbalance of redox homeostasis in the cell. For example, Au@Pt nanorods have been shown to oxidize ascorbic acid [48]. There are numerous reports and reviews concerning the oxidative stress-related mechanisms and effects induced by metallic nanoparticles. At the same time, there are several strategies to overcome this: not always desired property of nanoparticles or even giving nanoparticles the antioxidant properties [49; 50].