# Metal Nanozymes: New Horizons in Cellular Homeostasis Regulation
## 9 Nanozymes Combating Pathogens
The pseudopodia-like surface of the COF allowed the system to efficiently trap bacteria to enhance further the therapeutic efficacy of the MOF-based nanozyme [263]. Nanozymes are also regarded as potential antiviral agents. The classical iron oxide (Fe\({}_{3}\)O\({}_{4}\)) nanoparticles are well-known double-enzyme-mimics, showing peroxidase and catalase activities [266]. These nanoparticles are currently used for bioseparation, biosensing, bioimaging, drug delivery, and hyperthermia therapy, primarily because of their unique magnetic properties [266]. Recently, [PERSON] et al. used Fe\({}_{3}\)O\({}_{4}\) NPs to catalyze the inactivation of the influenza virus by targeting their lipid envelope [267] (Figure 12). In [PERSON]'s work, the Fe3O4 NPs (IONs), characterized by lipid peroxidation activity, progressively initiated the breakdown of the viral lipid envelope to destroy adjacent proteins (e.g., haemagglutinin, neuraminidase, and matrix protein 1) and cause concomitant structural damage. Thus, IONs impair the various structures and functions of the virus, resulting in unsuccessful infection of the host cells, ultimately inducing inactivation of influenza A viruses. In mice (BALB/c) infected withH5N1 virus, bodyweight reduction by over 20% during the 14 day infection period was abolished upon treatment with 4 mg/mL IONzymes. IONs can be also used to develop new catalytic mucosal vaccine adjuvants by exploiting its POD-like activity in acidic lysosomes to direct DC maturation. Mucosal vaccination to protect against influenza enhanced by a catalytic ION-based immune adjuvant has recently been elaborated by [PERSON] et al. [268], who designed a new mucosal vaccine based on the combination of chitosan (CS) functionalized iron oxide nanozyme and H1N1 whole inactivated virus (WIV). First, CS-IONzyme was synthesized  
Figure 12: Schematic of viral lip peroxidation by IONzymes for virus inactivation. IONzymes directly contact influenza A virus particles and collapse viral lipid envelope via enhancing the level of lipid peroxidation, which further produces free radicals to destroy the neighboring proteins, including hemagglutinin, neuraminidase, and matrix protein 1 and then impair various viral structures and functions, resulting in a failed infection into host cells. Reprinted from [267], with the permission of [[https://www.thno.org/](https://www.thno.org/)]([https://www.thno.org/](https://www.thno.org/)) (accessed on 6 September 2021). by a solvothermic method in which CS in the reaction system acted as both a ligand and a surface functionalization factor. CS was shown to cause a positive surface charge of IONzyme increasing potential antigen delivery. In a mouse model, CS-IONzyme was shown to have good biosafety. When mice were immunized intranasally with CS-IONzyme and H1N1 WIV complexes, the amount of the CS-IONzyme-H1N1 WIV complex was about 30-fold increased on the nasal mucosa compared to the H1N1 WIV only formulation after 15 min of incubation. The complex adhered stably to the mucosa surface. Furthermore, in in vivo study, CS-IONzyme facilitated H1N1 WIV to enhance CCL20-driven submu-cosal dendritic cell (DC) recruitment and transepithelial dendrite (TED) formation for viral uptake via the toll-like receptor (TLR) 2/4-dependent pathway. Moreover, IONzyme catalyzed a ROS-dependent DC maturation, which further enhanced the migration of H1N1 WIV-loaded DCs into the draining lymph nodes for antigen presentation. In result, CS-IONzyme-based nasal vaccine triggered an 8.9-fold increase in IgA-mucosal adaptive immunity in mice, providing a 100% protection against influenza, while only a 30% protection by H1N1 WIV alone (Figure 13). Figure 13: Schematic of proposed mechanism for enhancing antigen-specific immune response by the CS-IONzyme-based influenza vaccine. CS-IONzyme first enhances the adhesion levels of H1N1  
WIV to nasal mucosa after intranasal immunization of CS-IONzyme-based influenza vaccine in mice.