# Metal Nanozymes: New Horizons in Cellular Homeostasis Regulation
## 4 Strategies in the Quest for New Nanozymes
Interestingly, Mnf was found to be highly specific to H\({}_{2}\)O\({}_{2}\) as there was a significant decrease in the activity when cumene hydroperoxide or t-butyl hydroperoxide was used as substrates. The observed selectivity was attributed to the availability of active sites on the surface specific to small molecule H\({}_{2}\)O\({}_{2}\) and not bulky organic peroxides. In turn, in ceria-vanadium systems, a combination of the surface composition involves vanadium species (polymeric VOx and CeO\({}_{2}\) acting as Lewis acid sites, whereas CeO\({}_{4}\) act like Bronsted acid sites). Hence, [PERSON] et al. [117] suggested that the duality of both V-containing species (i.e., VOx and CeO\({}_{4}\)) can explain synergetic effects and can widen the operating window. A cerium vanadate (CeVO\({}_{4}\)) nanozyme can substitute the function of superoxide dismutase 1 and 2 (SOD1 and SOD2) in the neuronal cells even when the natural enzyme is downregulated by specific gene silencing. The nanozyme prevents the mitochondrial damage in SOD1- and SOD2-depleted cells by regulating the superoxide levels and restores the physiological levels of the antiapoptotic Bcl-2 family proteins [118]. Combining different oxides gives additional catalytic potential. [PERSON] et al. [119] constructed a manganese oxide composite with V\({}_{2}\)O\({}_{5}\) nanowires decorated with MnO\({}_{2}\). V\({}_{2}\)O\({}_{5}\) nanowire served as GPX mimic, while MnO\({}_{2}\) nanoparticle was used to mimic SOD and CAT. To assemble V\({}_{2}\)O\({}_{5}\) nanowires with MnO\({}_{2}\) nanoparticles, polydopamine (pDA) was used to combine two nanomaterials. In this way, the obtained V\({}_{2}\)O\({}_{5}\)@pDA@MnO\({}_{2}\) nanocomposites could serve as a multinanozyme model to mimic the intracellular enzyme-based antioxidativeative process. Moreover, pDA can also serve as an antioxidant to remove ROS [120]. Thus, by combining the antioxidant capacity of nanozymes and pDA, the V\({}_{2}\)O\({}_{5}\)@pDA@MnO\({}_{2}\) nanocomposites exhibited a synergistic ROS-scavenging effect that would protect cell components from oxidative damage. To further explore the potential of nanocomposites, a mouse model of phorbol 12-myristate 13-acetate (PMA)-induced otitis was designed. The results showed that V\({}_{2}\)O\({}_{5}\)@pDA@MnO\({}_{2}\) nanocomposites can be effective in lowering ROS levels as well as ameliorating the adverse effects caused by inflammation in mice. More recently, [PERSON] et al. [84] followed the idea of oxidative protection in cells designing CeO\({}_{2}\) conjugated with Mn\({}_{3}\)O\({}_{4}\) nanoparticles. The authors presented a very interesting emerging insight into the principles governing the structural physico-chemistry of nanomaterials. Namely, they managed to use the possibility of tuning the surface strain of metallic nanoparticles to modify their redox potential. Manganese ions deposition on the surface of CeO\({}_{2}\) nanocrystals caused the formation of strained layers of Mn\({}_{3}\)O\({}_{4}\) islands, increasing the number of oxygen vacancies in the CeO\({}_{2}\) phase. This feature enhanced the efficiency of oxygen adsorption on the surface of the nanocrystals, allowing for more effective removal of ROS. As a result, nanoparticles administered in vitro to hematopoietic intestinal stem cells protected them from radiation-induced ROS damage. In the mouse model, CeO\({}_{2}\)/Mn\({}_{3}\)O\({}_{4}\) nanocrystals prevented radiation-induced multiorgan damage in vivo and improved survival after total body irradiation. An important issue concerning metallic particles is their stabilization and biocompatibility. One method is the use of surfactants such as poly(acrylic acid) (PAA) [121]. Citrate-capped PtNPs were also shown to have SOD, CAT, and peroxidase-like properties that can reduce intracellular increased ROS levels in genetic model hyperoxia (krit1-ko MEF cells), protecting cell components from oxidative stress [122]. Similarly, citrate-capped nanocrystals of Pd can serve as both CAT and SOD mimics [123].