# Metal Nanozymes: New Horizons in Cellular Homeostasis Regulation
## 8 Metal Nanozymes in Cancer Treatment
found that the generation of \({}^{1}\)O\({}_{2}\) by MnWOX-PEG was much higher under the same US irradiation conditions than TiO\({}_{2}\) and PpIX nanoparticles. Mechanical effects of SDT mostly include the cavitation and sonoporation effect. Cavitation is a complex mechanism closely related to gas oscillation and generates ROS by inducing water thermal dissociation. During exposure to the US, gas bubbles rapidly collapse, and then the cavitation of inertial induces the release of energy, producing high temperature and pressures, leading to cell necrosis or producing strong shock waves, resulting in the mechanical damage for cell destruction. The sonoporation effect refers to the formation of pores in the cell membrane under US irradiation. These formed pores allow for the transfer of molecules and NPs into cells. In that way, the sonoporation effect could increase the uptake and accumulation of drug molecules, genes, or NPs. The last mechanism is the thermal effect trigger by increasing tissue temperature due to the absorption of US energy to destroy tumor cells. To increase the therapeutic responses to SDT, ultrafine titanium monoxide nanorods (TiO\({}_{1+\text{x}}\) NRs) were used by [PERSON] et al., with great improvement of sonosensitization and Fenton-like catalytic activity [231] (Figure 9). In addition, the authors modified conventional TiO\({}_{2}\) nanoparticles with the PEG\(-\)TiO\({}_{1+\text{x}}\) NRs resulted in a much more efficient US-induced generation of ROS. On the other hand, PEG-TiO\({}_{1+\text{x}}\) NRs also exhibit horseradish-peroxidase-like nanozyme activity and can produce hydroxyl radicals (\({}^{\bullet}\)OH) from endogenous H\({}_{2}\)O\({}_{2}\) in the tumor. This cancer treatment strategy, consisting of the conversion of hydrogen peroxide (H\({}_{2}\)O\({}_{2}\)) into a hydroxyl radical (OH), is gaining popularity in recent times and has been called chemodynamic therapy (CDT). The hydroxyl radical is the most harmful ROS produced in the Fenton-like reaction, and its high overproduction induces apoptosis and cell necrosis. [PERSON] et al. [232] tackled the toxicity of CuO NPs, which is the limitation for CuO NPs implementation in cancer therapy [233; 234]. At the in vitro level, the authors demonstrated the cytotoxicity in a dose-dependent manner, oxidative stress, and apoptosis response of CuO NPs on human hepatocellular carcinoma HepG2 [232]. Their study showed that tumor suppressor gene p53 and apoptotic gene caspase-3 were upregulated due to exposure to CuO NPs. Similar in vitro studies aimed at apoptosis induction were performed by [PERSON] et al. [235]. The authors targeted mitochondria with AuNP conjugated with turbo green fluorescent protein (mitoTGFP) harboring an amino-terminal mitochondrial localization signal and investigated its apoptosis effects on the human breast cancer cell line Jint-1. Fluorescence and transmission electron microscopy revealed that Au nanoparticle conjugates targeted the mitochondria, causing partial rupture of the outer mitochondrial membrane and cell death. [PERSON] et al. [236] published information about metal-oxidase-based nanozymes with peroxidase-like activity triggering a novel cell death through an ATP-citrate lyase (ACLY)-dependent rat sarcoma viral oncogene (RAS) signaling mechanism and termed it as nanopotsis (a term proposed by authors). They examined 11 representative nanomaterials  
Figure 9: Schematic diagram of ultrafine TiO1+x NRs used as a novel sonosensitizer for SDT/CDT of cancer. Reprinted from [231], with the permission of the American Chemical Society. (Cu(OH)\({}_{2}\), V\({}_{2}\)O\({}_{5}\), Ag, Fe\({}_{2}\)O\({}_{3}\), ZnO, SiO\({}_{2}\), ZnO, TiO\({}_{2}\), and Fe\({}_{3}\)O\({}_{4}\) characterized by different dimensions) at the human HepG2 hepatoma cells treatment study.