In recent years, oxidoreductase, which accounts for the largest proportion of nanoenzymes, has been widely used in the monitoring and treatment of a variety of brain diseases^[26⇓~28]. ROS has a dual role in the tumor environment: on the one hand, ROS in a certain concentration range can promote proto-cancer signaling, so that cancer cells can proliferate, survive, and adapt to hypoxic environment; On the other hand, high concentration of ROS can enhance oxidative stress response and induce cancer cell death^[29]. Because cancer cells are highly sensitive to ROS concentrations, redox nanozymes can be used to treat brain cancer by regulating the concentration of ROS (fig. 1). At the same time, nanomedicine anticancer schemes with ROS as drug delivery enhancers and cancer cell death inducers have also received extensive attention^[30].

Glioblastoma is the most common and aggressive type of brain tumor. Most of these tumors affect only the brain, and a small number of lesions involve the brain stem, cerebellum, and spinal cord, showing a diffuse growth pattern^[31]. At present, most of the studies on nanoenzyme and brain cancer therapy are based on glioblastoma. Mansur et al. Synthesized a new type of hybrid nanocatalyst by coupling natural enzyme (GOx) and single crystal iron oxide nanoparticles (inorganic nanoenzyme)^[32]. The killing effect of the nanoenzyme on human glioblastoma cells (U87MG) was tested in vitro, and it was proved that the nanoenzyme could increase the concentration of ROS through a cascade reaction and induce the iron death of cancer cells. It is worth noting that this nanozyme-induced cell death is more pronounced in brain cancer cells than in normal brain cells because the Tumor microenvironment (TME) is an acidic environment.

Combining traditional therapies with ROS inducers may also be an effective cancer treatment strategy^[33]. The hypoxic condition of TME and the inefficient synthesis of O₂ hinder the therapeutic effect of Sonodynamic therapy (SDT) to some extent. Considering this factor, Liu et al encapsulated sonosensitizer IR780 and catalase active nanomaterial MnO₂ in PLGA, and then connected Angiopep-2 to synthesize a multifunctional nanoenzyme, and carried out related experiments in glioma cell line U87MG and brain capillary endothelial cell line (Bend.The results showed that MnO₂ reacted with high levels of hydrogen protons, H₂O₂ and glutathione (GSH) in the tumor microenvironment, continuously produced oxygen and consumed GSH, which greatly enhanced the therapeutic effect of SDT and significantly inhibited tumor growth and distal metastasis^[34]. Mansur et al. Constructed an inorganic-inorganic dual-nanoenzyme system with AuNP @ TSC as Oxidase (OXD) nanoenzyme and Co-MION @ CMC as Peroxidase (POD) nanoenzyme^[35]. It triggers a biocatalytic cascade reaction in glioblastoma TME to achieve magnetothermal-chemical combination therapy. The system has high biocompatibility and targeting, and is expected to reduce the side effects caused by conventional chemotherapy.

Nanozyme, which has multiple enzymatic activities, has also been shown to have good anti-tumor effects^[36]. Muhammad et al. Controlled the active center of monatomic iron through the precise coordination of nitrogen and carbon, and connected Angiopep-2 to synthesize an iron monatomic nanoenzyme, Fe-CDs @ Ang, supported by ultra-small carbon dots, which showed a variety of enzymatic activities^[37]. Firstly, Fe-CDs @ Ang accumulates in acidic endosomal lysosomes (pH 4 ~ 5), showing OXD and POD activities, hindering lysosomal degradation and activating autophagy; In addition, Fe-CDs @ Ang can also exert the activities of Catalase (CAT), Superoxide dismutase (SOD) and glutathione peroxidase (GPx), act as ROS regulators, enhance autophagy, alleviate the hypoxic environment of TME, and further promote the death of malignant glioma cells.

Because of the precision and targeting of nanoenzyme-induced ROS toxicity therapy for cancer cells, it has little effect on advanced metastatic tumors. Wang et al. Designed a smart drug delivery system with dual temperature and pH-sensitive responses to the tumor microenvironment to suppress primary and metastatic cancers by releasing a small molecule immunomodulator, R848, to enhance systemic immune response, activate dendritic cells, and improve the function of CD8⁺T cells^[38]. Unfortunately, there are few studies on enhancing the body's immune system's anti-tumor immunity in the field of brain cancer. Therefore, the application of this regimen to advanced brain cancer may be an effective treatment.

Similarly, nanoenzymes also have problems such as being easily recognized by the body as foreign bodies, causing immune responses, and premature leakage of a single nanomedicine before it reaches the site of disease. In this regard, Zhu et al. Coated the erythrocyte membrane on the surface of Ru@MnO₂ nanoenzyme, and then loaded the antitumor drug doxorubicin (DOX) to enhance the biocompatibility of nanoenzyme through the erythrocyte membrane and prolong the circulation time in the blood, and constructed a nanoenzyme with on-demand release ability^[39]. The nanoenzyme system can better relieve the hypoxic environment in TME, and play a better synergistic anticancer effect by combining with traditional treatment methods such as chemotherapy.

Nanozyme is expected to become a highly effective solution for brain cancer treatment, not only because it is directly involved in anti-cancer, but also because its application in brain cancer cell detection is a developable path.

At present, the detection of brain cancer by NANase mainly depends on the specific receptors of various proteins on cancer cells. Based on the principle that efficient oxidation of peroxidase substrates produces a color reaction and that transferrin receptor (TfR) is overexpressed in glioblastoma cells, Weerathunge et al. Bound superparamagnetic iron oxide nanoparticles to transferrin (Tf) and monitored the cellular expression profile of TfR^[40,41][42]. Because the difference in TfR expression between U87MG cells and fibroblasts produces a distinct colorimetric response, this system can be used as an intuitive and simple tool for brain cancer detection. Kip et al. Proposed a new method to determine the concentration of brain cancer cells by the color reaction of peroxidase active nanoenzyme and 3,3 ', 5,5' -tetramethylbenzidine (TMB)^[43][44]. They prepared a HA@Fe₃O₄@SiO₂ microsphere that interacts with CD44 receptors on primary brain tumor cells via hyaluronic acid (HA), allowing the cells to take up the microsphere via endocytosis. The higher the concentration of cancer cells, the less the number of microspheres remaining in the medium, and the lower the peroxidase activity. The enzyme activity was determined by the chromogenic reaction of peroxidase and TMB with Fe₃O₄ nanoparticles, and then the concentration of cancer cells was determined.

Alzheimer's disease is characterized by abnormal accumulation of amyloid β (Aβ) and oxidative stress. In pathological settings, activated M1-type microglia mediate neurovascular unit dysfunction due to aberrant phagocytosis leading to enhanced Aβ deposition^[45]. Considering that nanozymes are mostly absorbed by microglia, Ren et al. Designed a multifunctional nanozymes （TPP-MoS₂ quantum dots), which showed SOD and CAT activities.At the same time, it has mitochondrial targeting, which can convert microglia from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype, restore its phagocytosis of Aβ and nerve repair function, and effectively reduce the neurotoxicity caused by Aβ aggregation^[46].

In order to overcome the obstruction of blood-brain barrier to nanoenzyme, Gong et al. Combined borneol, a traditional Chinese medicine that can open the blood-brain barrier through neurotransmitters, with two nanoenzymes, selenium nanoparticles and polydopamine, to prepare a nanoenzyme system with SOD and CAT activities^[47]. Experiments show that the system can effectively remove ROS and reactive nitrogen species (RNS) inside and outside cells and alleviate oxidative stress damage; At the same time, it promotes the transition of microglia from M1 phenotype to M2 phenotype. Jia et al. Also used borneol. They combined borneol with octahedral palladium nanoparticles (Pd-NPs) with excellent antioxidase-like activity and excellent biocompatibility, and found that in addition to reducing oxidative damage, the system could also reduce the content of Ca²⁺, maintain mitochondrial membrane potential, and further protect mitochondria^[48]. Bai et al. Used the brain cell targeting effect of extracellular vesicles and rabies virus peptide (RVG) to load resveratrol and platinum nanoenzyme particles, a high-performance antioxidant with multiple enzyme activities, and used this composite nanoenzyme in Alzheimer's disease. Experiments showed that the composite nanoenzyme could effectively penetrate the blood-brain barrier, protect mitochondria, and reduce Aβ aggregation^[49]. In addition, metal ions, especially Cu²⁺, are related to the formation of Alzheimer's disease, and the imbalance of Cu²⁺ in the environment binds to Aβ, which may cause the deposition of Aβ and promote the production of ROS^[50]. Du et al. Designed 2D ultrathin niobium carbide （Nb₂C） nanosheets artificial nanoenzyme to selectively capture Cu²⁺, which effectively inhibited the coordination between Cu²⁺ and Aβ aggregates and protected neuronal cells from Cu²⁺ related toxicity^[51].

At present, an important method to detect Alzheimer's disease is to detect Aβ content by ELISA kit. In order to solve the problem of low sensitivity of commercial ELISA kits to Aβ (1 ~ 40), Lyu et al. Used Fe-N-C single-atom nanoenzymes (SANs) to replace the natural enzyme HRP in ELISA kits^[52]. Due to the high surface energy, high metal atom utilization, uniform active sites, special geometry, significant catalytic activity and good stability of SANs, the sensitivity of the improved SAN-LISA kit for Aβ detection was 0. 88 pg/mL, which was much higher than that of the commercial ELISA (9. 98 pg/mL). Therefore, the SAN-LISA kit is expected to be widely used in Alzheimer's disease monitoring.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease^[53]. Its pathological features include dopaminergic neuron degeneration, striatal Dopamine (DA) reduction, and α-synuclein (α-syn) misfolding and aggregation. The clinical manifestations are motor disorders such as hand tremor, bradykinesia, myotonia, difficulty in balancing posture, and non-motor symptoms such as depression and sleep disorders.

Parkinson's disease has been studied by treating cells with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenylpyridine (MPP +) to induce dopaminergic neurodegeneration, thus mimicking the pathological characteristics of Parkinson's disease. Singh et al. Prepared a Mn₃O₄ nanoenzyme, which has SOD, CAT and GPx-like activities, can regulate ROS levels, alleviate oxidative stress, and effectively inhibit MPP + -induced apoptosis due to the mixed oxidation state （Mn²⁺/Mn³⁺） of manganese in the material, high stability against irreversible oxidation, large surface area and pore size^[54]. Wang et al. Considered the SOD and CAT enzyme activities of Polydopamine (PDA), combined PDA with selenocysteine to prepare a nanocomposite PDASeCys with GPx activity, which has good free radical scavenging ability and antioxidant enzyme activity^[55]. Cell experiments show that the nanocomposite can effectively reverse MPP + -induced cell death, reduce ROS levels, change mitochondrial membrane potential, and fundamentally maintain redox balance; In animal experiments, the motor and cognitive levels of Parkinson's disease mice with dopaminergic neurodegeneration were restored and DA levels were effectively maintained by injecting PDASeCys into the substantia nigra. Similarly, the penetration of nanozymes across the blood-brain barrier is crucial in the treatment of Parkinson's disease. Li et al. Accelerated the catalysis of Bi₂Se₃ by Au, mimicking antioxidant enzymes (e.g. CAT, SOD, GPx, and POD), which effectively reduced ROS levels in MPTP-induced PD model^[56]; Lactoferrin is then used to modify the nanoenzyme to enhance receptor-mediated endocytosis in the blood-brain barrier to achieve targeted therapy for Parkinson's disease.

The change of DA can also be used as a detection index of Parkinson's disease. Zhu et al. Prepared a nanomaterial composed of Prussian blue nanoparticles loaded with MoS₂^[57]. This nanozyme can catalyze TMB to blue oxidized TMB in the presence of H₂O₂. DA can inhibit the oxidation of MB and make the blue solution fade and become colorless. By this method, DA in the range of 0 to 300 µmol/L can be qualitatively and quantitatively analyzed.

Promoting neurogenesis through neuronal differentiation is a promising approach for the treatment of neurodegenerative diseases. Xia et al. Found that polyethylene glycol （PEG）-Fe₃O₄ nanozyme could play an antioxidant role and promote the expression of autophagy-related proteins, thereby maintaining the integrity of the blood-brain barrier, inhibiting apoptosis, and promoting the differentiation of hippocampal neural stem cells in aged mice^[58]. Because of the inevitable oxidative stress during neurogenesis, Yu et al. Designed ceria-modified metal-organic framework nanoparticles to co-deliver siSOX9 and retinoic acid (RA) to promote neurogenesis^[59]. On the one hand, the synergistic effect of siSOX9 and RA can well promote the directional differentiation of neurons. On the other hand, ceria exerts SOD and CAT activities to reduce the inflammatory damage to newborn neurons.

Hydrogen sulfide （H₂S） I s a modulator of age-related neurodegenerative diseases of the central nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Down syndrome. H₂S can resist the influence of aging by activating SOD, CAT and Gpx to limit the process of free radical reaction, and then regulating the expression of apoptosis-related genes Bax, Bcl-2 and p53, thus exerting its antioxidant effect. Wang et al. Designed an optical monitoring platform to monitor the changes of H₂S content in the brain, which is helpful to study the mechanism of degenerative diseases^[28]. Prussian blue nanoparticles with strong oxidase-like activity were synthesized and mixed with artificial cerebrospinal fluid (aCSF) and TMB, and the continuous light intensity distribution in the digital signal was recorded for quantitative analysis of H₂S. Subsequently, they also synthesized a molybdenum-polysulfide-deposited nickel-iron bimetallic Prussian blue analogue-based hollow nanocage with multiple enzymatic activities, which was also used for optical monitoring of H₂S^[60]. The peroxidase and lactase activities of the nanocage are 37 times and 27 times higher than those of the original Prussian blue analogue, respectively. In addition, the nanoenzyme showed higher stability than the native enzyme in the environment of strong acid, high temperature and high salt concentration.

Traumatic brain injury (TBI) is a kind of brain injury caused by mechanical force. The primary and secondary injuries of TBI may lead to permanent functional defects of the nervous system and even death^[61]. Oxidative stress is the earliest type of secondary injury in TBI. ROS and reactive nitrogen species (RNS) are generally produced within a few minutes after TBI, which can easily cause central nervous system damage^[62]. Mu et al. Developed a carbon source nanoenzyme, which showed high antioxidant activity and high selectivity for RNS^[63]. After intravenous injection of the nanozyme, the levels of ROS and RNS in the brain tissue of mice affected by TBI were significantly reduced. They also prepared an oligomer nanoenzyme (O-NZ) with ultrafast electron transfer rate, which significantly improved the catalytic activity^[64]. O-NZ reduced neuroinflammation in mice with acute brain injury, resulting in an increase in 1-month survival from 50% to 90%. At the same time, the experiment proves that the nanoenzyme has a good effect on the long-term neurocognitive recovery of mice.

Yan et al. And Zhang et al. Conducted experiments from the perspective of non-invasive treatment^[65][66]. They developed a series of nanoenzyme bandages based on CeO₂ to protect neurons by removing ROS and reducing inflammation in the neuronal system after brain trauma. The nano-enzyme bandage has lasting catalytic activity and can effectively promote the healing of wounds. In addition, they combined nanoenzymes such as RhN₄, VN₄ and Fe-Cu-N₆ with polyglycolic acid (PGA) suture to develop MNx suture, which was applied to the scalp of live mice with traumatic brain injury^[19]. The MNx suture maintains the original high enzyme activity, not only can effectively control the levels of superoxide dismutase and GSH after scalp injury, but also has a significant effect on removing lipid peroxides and H₂O₂ accumulated after brain injury. Among them, RhN₄ and VN₄ significantly down-regulated the levels of proinflammatory cytokines; VN₄ and Fe-Cu-N₆ have better efficacy in promoting the formation of new blood vessels.

In order to improve the targeting of nanoenzyme to the disease site, He et al. Used GSH and lysine as raw materials to prepare an ultra-small organic nanoenzyme by condensation and carbonization under microwave conditions according to the optimal ratio, which could gradually aggregate through spontaneous reaction in the ROS-rich environment of TBI mouse brain^[67]. In this environment, the size of the nanozyme changed to 75 and 100 times of the original size, respectively, but the enzymatic activity remained unchanged.

Stroke, also known as stroke, is a neurological disease related to blood vessel blockage. Stroke can lead to depression and dementia and is the second leading cause of death worldwide. Cerebral ischemia caused by thrombosis accounts for about 87% of stroke cases^[3]. Hypoxic environment in the brain can induce a large number of inflammatory factors, resulting in neuroinflammation and neuronal death, and a large number of ROS will be produced after reperfusion, which will cause serious damage to cell structure and blood-brain barrier. At present, nanoenzyme-based therapies mainly focus on improving neuroinflammation and ROS clearance, and some researchers have improved the properties and functions of nanoenzyme drugs from a new perspective, which is expected to achieve better therapeutic efficacy^[68,69].

First of all, the role of various metal ions in the inflammation of ischemic stroke has been concerned. Considering the induction of neuronal death by the high Zn²⁺ environment that inhibits ischemic stroke, Huang et al. Prepared a multi-active nanoenzyme Ce/Zeo-NMs with adsorption effect^[70]. On the one hand, the accumulation of Zn²⁺ is reduced by adsorption; On the other hand, the superoxide dismutase activity and catalase activity of nanozyme are used to combine superoxide and H₂O₂ to reduce the volume of cerebral infarction, improve the survival rate of neurons and alleviate the deterioration of blood-brain barrier. Huang et al. Used human serum albumin to modify Mn₃O₄ NANase and improved the biocompatibility and stability of NANase^[71]. In addition, manganese ions are released while scavenging ROS, which increases the level of superoxide dismutase 2 in vivo and promotes ROS scavenging.

In addition, due to the complex pathological environment after stroke, the composition of the body's antioxidant system is also more complex, including a variety of enzymes and enzymatic reactions. Tian et al. Constructed a multienzyme cascade antioxidant system by entrapping the diiron atom nanoenzyme （Fe₂NC） in a selenium-containing MOF (Se-MOF) shell^[72]. The GPx activity of Se-MOF and the SOD and CAT activities of Fe₂NC can effectively mimic the natural antioxidant system. The nanoenzyme antioxidant system can reduce oxidative damage after cerebral ischemia-reperfusion and inhibit neuronal apoptosis by removing intracellular ROS and inhibiting ASK1/JNK apoptosis signaling pathway.

Yan et al. Added Fe₃O₄ nanoenzyme to the diet to improve the local redox status by reducing malondialdehyde and increasing Cu/Zn SOD, and promoted the expression of key proteins ZO-1 and Claudin-5 related to the tight junction of endothelial cells, thus alleviating the injury of endothelial cells and promoting the recovery of blood-brain barrier^[73].

It can not be ignored that due to the influence of blood-brain barrier, the delivery of nanoenzyme drugs to ischemic brain is still insufficient. After ischemic stroke, neutrophils are attracted to the damaged brain and interact with the inflamed cerebral microvascular endothelial cells due to the expression of related proteins on the neutrophil membrane. Therefore, Feng et al. Realized the targeted delivery of drugs with the help of neutrophil membrane-like membrane coated mesoporous Prussian blue nanoenzyme^[74]. The drug is taken up by microglia, promotes the polarization of microglia to M2 type, reduces neutrophil aggregation, reduces neuronal apoptosis, and achieves the effect of reducing brain injury. Zhao et al. Synthesized a manganese dioxide nanoenzyme embedded with Tf by biomineralization, loaded with clinical neuroprotective agent edaravone (Eda), and obtained Eda-MnO₂@Tf（EMT） nanoenzyme^[75]. The nanoenzyme can recognize TfR on microvascular endothelial cells, cross the blood-brain barrier through endocytosis, target the lesion area, scavenge free radicals, reduce inflammation, and effectively protect neurons.

In addition, nanozymes can also be used to monitor ischemic stroke. Liu et al. Obtained ZIF-67/Cu_0.76Co_2.24O₄ nanospheres by rationally adjusting the ratio of cobalt dimethylimidazole (ZIF-67) to Cu(NO₃)₂^[27]. The nanomaterial has the activities of POD, GPx, SOD and laccase, based on which they established an on-line electrochemical continuous monitoring system with good linearity in the range of 0.5 ~ 20 μmol/L and a detection limit of 0.15 μmol/L, and successfully recorded the changes of neurotransmitters before and after cerebral ischemia in rats. Cheng et al. Synthesized nanoenzymes INAzymes by embedding two cascade catalysts, molecular catalyst Hemin and natural enzyme glucose oxidase, into zeolitic imidazolate framework (ZIF-8) nanostructures at the same time, which greatly improved the reaction rate^[26]. In addition, they introduced microfluidic technology, combined with in vivo microdialysis technology and fluorescence microscopy, to build an integrated sensing platform, which successfully realized the continuous monitoring of brain glucose dynamic changes after cerebral ischemia-reperfusion in vivo.

Malaria is a disease caused by Plasmodium. Cerebral malaria occurs mostly in patients with falciparum malaria, with rapid deterioration and high mortality. Considering that reactive oxygen species may cause severe damage to the blood-brain barrier in the pathogenesis of cerebral malaria, Zhao et al. Prepared a ferritin nanoenzyme (Fenozyme) composed of recombinant human ferritin (HFn) protein shell coated with Fe₃O₄^[76]. HFn can bind to the HFn receptor expressed on the endothelial cells of the blood-brain barrier, thereby specifically targeting the blood-brain barrier, exerting CAT activity, and effectively inhibiting the level of ROS in vivo. In addition, Fenozyme can polarize macrophages in the liver to M1 phenotype, and may also achieve combination therapy with artemether to promote the elimination of malaria. Due to the difficulty of oral medication in cerebral malaria patients, Prabhu et al. Prepared nanostructured lipid carriers loaded with malaria drug artemether-lumefantrine (ARM-LFN) for intravenous injection^[77]. The nanoenzyme exhibited a sustained drug release process, good biocompatibility and stability, and excellent parasite clearance and malaria therapeutic efficacy. Therefore, the combination of nanomaterials and anti-malarial drugs may be a new strategy for the treatment of cerebral malaria.

Epilepsy is one of the most common neurological diseases with complex causes, and the detailed pathophysiology and treatment mechanism are still unclear. However, epilepsy has the characteristics of recurrent seizures and brain dysfunction^[78]. Oxidative stress is a possible mechanism of epileptogenesis. Wang et al applied fluorescent nanodiamonds (FNDs), an enzyme mimic, to the study of epilepsy. FNDs have a variety of enzyme activities, which can inhibit the production of free radicals and lipid peroxidation products by positively regulating the Nrf2/ARE pathway, reduce oxidative stress, and protect epileptic astrocytes^[79]. In addition, FNDs have good optical properties, which provide convenience for tracing their localization in cells and studying their mechanism of action.