# Metal Nanozymes: New Horizons in Cellular Homeostasis Regulation
## 4 Strategies in the Quest for New Nanozymes
Specifically, the peroxidase-mimicking activity of the porous LaNiO\({}_{3}\) nanocubes with Ni\({}^{3+}\) was, respectively, about 58-fold and 22-fold higher than that of NiO with Ni\({}^{2+}\) and Ni nanoparticles with Ni\({}^{0}\). The oxidation state was very important for cerium oxides' [93; 94] and iron oxides' [95] enzyme mimicking activities. Fe\({}_{3}\)O\({}_{4}\) nanoparticles are one of the most classic nanozymes showing peroxidase and catalase-like activity [14]. Enzyme-mimicking iron-oxide-based nanomaterials can be synthesized in various conformations, yet the decisive factor that allows one to fully reveal the iron oxide catalytic potential seems to rely on the application of the proper ligand environment. Again, the observation of nature prompts the application of the amino acid ligand entourage. For example, distal histidine, highly conserved in nearly all globins and all heme peroxidadases, is important in tuning the affinity of these proteins ligands. In globins, the distal His stabilizes O\({}_{2}\) binding and has possible subsidiary functions of preventing autoxidation and discrimination against CO binding to the heme Fe. In peroxidadases, the distal His has the nearly opposite role of activating bound H\({}_{2}\)O\({}_{2}\) for heterolytic bond cleavage [96]. Indeed, as shown by [PERSON] et al. [97], covalently modifying the histidine residues on the Fe\({}_{3}\)O\({}_{4}\) surface resulted in nanozymes having a significantly higher affinity for H\({}_{2}\)O\({}_{2}\) than that of unmodified Fe\({}_{3}\)O\({}_{4}\). As in the case of many other metaloxide nanozymes, the presence of metal in two different oxidation states on the surface of the nanozyme is crucial for enzymatic activity of Fe\({}_{3}\)O\({}_{4}\)-based nanozymes. Such a multivalent system brings the nanozymes functionally closer to the systems present in the active centers of various proteins, for example, those containing heme [98] or iron-sulfur clusters [5; 99; 100]. Prussian Blue (PB) nanoparticles and their analogues are organometallic structures (MOFs) composed of alternately arranged Fe\({}^{2+}\) and Fe\({}^{3+}\) atoms coordinated with cyanides. Due to this multivalent structure, they exhibit activity resembling those of catalytic sites in metals. Moreover, they possess other important properties such as highly porous structure and biocompatibility [101]. The property of PB nanoparticles to scavenge ROS is due to their affinity for hydroxyl radicals and their ability to mimic three enzymes: SOD, CAT, and peroxidase. Different oxidation states are responsible for the unique multicatalytic properties of these enzymes, which can be changed by the regulation of external potentials (PB has a low redox potential). The HRP-like (horseradish peroxidase) catalytic activity of PB is mainly due to the presence of ferrous ions [95]. For another instance, cerium (IV) oxide nanoparticles have been shown to exhibit SOD properties due to their mixed valence (Ce\({}^{3+}\) and Ce\({}^{4+}\)) [102]. Interestingly, the ability of nanoceria to scavenge superoxide is directly related to higher cerium (III) concentrations at the surface of the particle, while the CAT mimetic activity correlates with a reduced level of cerium in the +3 state, in favor of the 4+ [93, 94]. Concluding, the catalytic mode of the nanozyme can be tuned by changing the oxidation state of the nanoparticle's surface. Another observation of nature implicates that the choice of the metal according to the observed natural effects can be useful in tuning the catalytic potential of nanozymes. For example, the research showed that natural Mn SOD works better than Cu/Zn SOD and Fe SOD [103], which suggests that it should also be similar in regard to manganese nanozymes. Indeed, [PERSON] et al. [104] obtained Mn\({}_{3}\)O\({}_{4}\) nanozymes, which dismutated superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals in vitro and protected live mice from ROS-induced ear-inflammation in vivo.