Multienzyme-like Activity Research Articles

The progress of research on the application of redox nanomaterials in disease therapy.

Redox imbalance can trigger cell dysfunction and damage and plays a vital role in the origin and progression of many diseases. Maintaining the balance between oxidants and antioxidants in vivo is a complicated and arduous task, leading to ongoing research into the construction of redox nanomaterials. Nanodrug platforms with redox characteristics can not only reduce the adverse effects of oxidative stress on tissues by removing excess oxidants from the body but also have multienzyme-like activity, which can play a cytotoxic role in tumor tissues through the catalytic oxidation of their substrates to produce harmful reactive oxygen species such as hydroxyl radicals. In this review, various redox nanomaterials currently used in disease therapy are discussed, emphasizing the treatment methods and their applications in tumors and other human tissues. Finally, the limitations of the current clinical application of redox nanomaterials are considered.

Oxygen Vacancy-Rich Amorphous BiVO4 Nanoparticles for Colorimetric Sensing

Defects in crystalline nanozymes play a critical role in enhancing their performances and related catalytic events. However, creating a high concentration of active and robust defects in well-explored crystalline metal oxides to achieve high-performance single-enzymatic activity is challenging. Herein, amorphous BiVO4 beyond traditional crystalline nanozymes is prepared via a facile solution-processed coprecipitation method favorable to large-scale manufacturing to mimic enzymatic properties. As expected, the specially designed amorphous material without any post-treatments has sufficient and robust oxygen vacancies, which are highly active in converting oxygen to reactive radicals (O2–•). Simultaneously, the negatively charged surface has a high affinity for the substrate, facilitating charge transfer between materials and substrates and, in turn, providing higher catalytic efficiency compared to the crystalline counterparts. Most importantly, the sample can only mimic oxidase-like activity rather than the multienzyme-like activity generally observed in most reported crystalline metal oxides, which is a step forward in the development of nanozymes. This amorphous BiVO4-based system is also evaluated for the sensitive and selective detection of l-cysteine. The study provides insight into nanozyme development and highlights the great potential of amorphous materials in addition to amorphous BiVO4.

Multienzyme-Mimicking Au@Cu2O with Complete Antioxidant Capacity for Reactive Oxygen Species Scavenging.

Most enzyme catalysts are unable to achieve effective oxidation resistance because of the monotonous mimicking function or production of secondary reactive oxygen species (ROS). Herein, the Au@Cu2O heterostructure with multienzyme-like activities is deigned, which has significantly improved antioxidant capacity compared with pure Cu2O for the scavenging of highly cell-damaging secondary ROS, i.e.,·OH. Experiments and theoretical calculations show that the heterostructure exhibits a built-in electric field and lattice mismatch at the metal-semiconductor interface, which facilitate to generate abundant oxygen vacancies, redox couples, and surface electron deficiency. On the one hand, the presence of rich oxygen vacancies and redox couple can enhance the adsorption and activation of oxygen-containing ROS (including O2·- and H2O2). On the other hand, the electron transfer between the electron-deficient Au@Cu2O surface and electron donor would promote peroxide-like activity and avoid producing ·OH. Importantly, endogenous ·OH could be eliminated in both acidic and neutral conditions, which is no longer limited by the volatile physiological environment. Therefore, Au@Cu2O can simulate superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione peroxidase (GPx) to form a complete antioxidant system. The deigned nanoenzyme is explored in the real sample world such as A549 cells and zebrafish. This work provides theoretical and practical strategies for the construction of a complete antioxidant enzyme system.

Metal-Based Nanozymes with Multienzyme-Like Activities as Therapeutic Candidates: Applications, Mechanisms, and Optimization Strategy.

Most nanozymes in development for medical applications only exhibit single-enzyme-like activity, and are thus limited by insufficient catalytic activity and dysfunctionality in complex pathological microenvironments. To overcome the impediments of limited substrate availabilities and concentrations, some metal-based nanozymes may mimic two or more activities of natural enzymes to catalyze cascade reactions or to catalyze multiple substrates simultaneously, thereby amplifying catalysis. Metal-based nanozymes with multienzyme-like activities (MNMs) may adapt to dissimilar catalytic conditions to exert different enzyme-like effects. These multienzyme-like activities can synergize to realize "self-provision of the substrate," in which upstream catalysts produce substrates for downstream catalytic reactions to overcome the limitation of insufficient substrates in the microenvironment. Consequently, MNMs exert more potent antitumor, antibacterial, and anti-inflammatory effects in preclinical models. This review summarizes the cellular effects and underlying mechanisms of MNMs. Their potential medical utility and optimization strategy from the perspective of clinical requirements are also discussed, with the aim to provide a theoretical reference for the design, development, and therapeutic application of their catalytic effects.

Nanoceria as an Electron Reservoir: Spontaneous Deposition of Metal Nanoparticles on Oxides and Their Anti-inflammatory Activities.

Designing metal-metal oxide heteronanostructures with synergistic and superior activities (unattainable in the case of a single entity) is of great interest for a wide range of technological applications. Traditional synthetic strategies typically require reducing agents, stabilizing ligands, or high temperature reductive treatment to produce oxide-supported metals. Herein, a facile noble metal deposition strategy is developed to produce silver, gold, and platinum nanocrystals on the surface of hollow mesoporous cerium oxide nanospheres without any pretreatment. Unlike the galvanic replacement reaction, the developed protocol employs the innate reductive potential of CeO2 to produce a high density of ultrafine noble metal nanocrystals homogeneously immobilized onto the surface of CeO2 nanospheres. The multienzyme-like activities (i.e., superoxide dismutase-like and catalase-like) of CeO2@metal nanostructures, originating from CeO2 and metal nanoparticles, were effectively utilized for anti-inflammatory therapies in two in vivo models. This oxygen vacancy-mediated reduction strategy can be generalized to produce diverse metal-metal oxide nanostructures for a wide range of applications.

Intrinsic Multienzyme-like Activities of the Nanoparticles of Mn and Fe Cyano-Bridged Assemblies.

This study investigates the intrinsic multienzyme-like properties of the non-stabilized nanocrystalline nanoparticles of manganese-doped Prussian blue (Mn-PB) nanozymes and Prussian blue (PB) nanozymes in chemical and electrocatalytic transformations of reactive oxygen species. The effect of manganese doping on the structural, biomimetic, and electrocatalytic properties of cyano-bridged assemblies is also discussed.

Single-Atom Pd/CeO2 Nanostructures for Mimicking Multienzyme Activities

The construction of nanozymes at the atomic level that hold structural stability and high enzyme-like activity is now a key factor in the optimization of an artificial enzyme. Single-atom metal/cerium oxide (CeO2)-based nanozymes have been demonstrated to possess a variety of enzymatic activities and radical scavenging abilities, which are mainly attributed to the single-atom active site, redox valence states, and abundant defect chemistry. Here, we developed a single-atom Pd/CeO2 nanostructure by aqueous phase synthesis that exhibits the advantages of high yield and good stability. The Pd/CeO2 nanostructure possesses peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) activities as well as reactive nitrogen species free-radical scavenging activity, exhibiting multienzyme-like activities and stability compared with CeO2 and other metal-based nanozymes. It is worth mentioning that the Pd/CeO2 nanostructure exhibits high POD-mimicking activity with a reaction rate of 0.88 μM/min, about 5 times higher than that of the CeO2 nanozyme. In addition, the CAT-like activity of the Pd/CeO2 nanostructure is excellent, and its scavenging rate of hydrogen peroxide reached nearly 100% at a concentration of 50 ng/μL. The present work shows that single-atom Pd substitution is a promising strategy for the design of CeO2 nanozymes to exert better effects on biomedical applications, especially with diseases related to oxidative stress.

Iron Phosphate Nanozyme-Hydrogel with Multienzyme-like Activity for Efficient Bacterial Sterilization.

Pathogenic bacteria infections have posed a threat to human health worldwide. Nanomaterials with natural enzymatic activity provide an opportunity for the development of new antibacterial pathways. We successfully constructed iron phosphate nanozyme-hydrogel (FePO4-HG) with the traits of positive charge and macropores. Interestingly, FePO4-HG displayed not only peroxidase-like activity under acidic bacterial infectious microenvironment but also superoxide dismutase-catalase-like synergistic effects in neutral or weak alkaline conditions, thus protecting normal tissues from the peroxidase-like protocol with exogenous H2O2 damage. Furthermore, the positive charge and macropore structure of FePO4-HG could capture and restrict bacteria in the range of ROS destruction. Obviously, FePO4-HG exhibited excellent antibacterial ability against MRSA and AREC with the assistance of H2O2. Significantly, the FePO4-HG + H2O2 system could efficiently disrupt the bacterial biofilm formation and facilitate the glutathione oxidation process to rapid bacterial death with low cytotoxicity. Moreover, FePO4-HG was unsusceptible to bacterial resistance development in MRSA. Animal experiments showed that the FePO4-HG + H2O2 group could efficiently eliminate the MRSA infection and present excellent wound healing without inflammation and tissue adhesions. With further development and optimization, FePO4-HG has great potential as a new class of antibacterial agents to fight antibiotic-resistant pathogens.

A multifunctional nanozyme-based enhanced system for tert-butyl hydroquinone assay by surface-enhanced Raman scattering.

An Au-based nanozyme composite (AuNPs/Cu,I) was constructed by using Cu,I-doped carbon dots (Cu,I-CDs) as the reducing agent as well as the nanozyme. Notably, AuNPs/Cu,I nanozyme not only possessed the intrinsic activity of mimicking enzymes of superoxide dismutase, peroxidase, and catalase at different conditions but was also employed as surface-enhanced Raman spectroscopy (SERS) enhancer. The combination of Cu,I-CDs and AuNPs promoted the electron transferability, leading to increased peroxidase-like activity and superoxide-like activity. Compared to the individual Cu,I-CDs and AuNPs nanozyme, the AuNPs/Cu,I composite demonstrated promising peroxidase-like activity by transferring electrons instead of generating OH. Interestingly, the multienzyme-like activity of AuNPs/Cu,I nanozyme could be finely tuned by changing the composition of Cu0/Cu+ and Au. Thetert-butyl hydroquinone (TBHQ) as the substrate could be catalyzed with AuNPs/Cu,I nanozyme to produce red substances, resulting in a significant Raman enhancement effect at the same time, showing good linear range from 0.11 to 10mg L-1. Overall, the current investigation provides a flexible and controllable way to design multifunctional nanozymes along with the Raman enhancement strategy based on the catalysis of nanozyme.

One-component nano-metal-organic frameworks with superior multienzyme-mimic activities for 1,4-dihydropyridine metabolism

Although a number of nanozymes have been developed, it is still difficult to develop single-component nanozyme with overall high multienzyme-like activities. In this study, the nanosized metal–organic frameworks (nano-MOFs) FePCN (PCN stands for porous coordination network) was synthesized by integrating zirconium and iron ions with different catalytic property on single-component MOFs and exhibited superior intrinsic multienzyme-like activities, namely oxidase-, peroxidase- and phosphatase-mimicking activity. The catalytic active sites of oxidase- and peroxidase-, and phosphatase-like activity of FePCN were Fe-centers and Zr-O clusters, respectively. Based on the intrinsic oxidase-like activity and the similarity of molecular structures between cytochrome P450 oxidase (CYP) cofactors and the organic linker in FePCN, FePCN exhibited high CYP-like activity to catalyze the oxidation of hypotensive drug 1,4-dihydropyridine (1,4-DHP) into diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (DDPD) and the yield of DDPD reached over 80%. Moreover, as peroxidase- and phosphatase-mimics, FePCN was successfully applied to detecting H2O2 under neutral condition and catalyzing the dephosphorylation of adenosine triphosphate (ATP), respectively. This study provides a feasible way for rational design one-component nanomaterials as multienzyme-mimics.

Facile preparation of four-in-one nanozyme catalytic platform and the application in selective detection of catechol and hydroquinone

Abstract Development of nanomaterials with multienzyme-like activities (nanozymes) via a simple way has attracted paramounting attention. Generally, enzymatic activity is closely related to the size, surface state, material type, etc. Bimetallic oxides are very appealing owing to their mixed valence and structural advantages. Herein, we reported an eco-friendly strategy to synthesize Co1.5Mn1.5O4 nanozyme via sol-gel method. This nanozyme functionally mimics four major enzymes, i.e. laccase, peroxidase (POD), oxidase (OXD), and catalase (CAT). Accordingly, a colorimetric sensing platform was designed to distinguish isomers of organic pollutants ‒catechol (CC) and hydroquinone (HQ) by using Co1.5Mn1.5O4 as the sole catalyst. In particular, laccase-like activity of Co1.5Mn1.5O4 enables it to directly oxidize CC into yellow o-benzoquinone with good linearity in the range of 1∼1000 μM and a detection limit of 0.35 μM. Meanwhile, HQ can discolor the oxidized substrate that was pre-oxidized with the aid of oxidase-like activity of the nanozyme (linear range: 0.05∼100 μM, detection limit: 0.04 μM). The established colorimetric method has been successfully utilized for selective sensing of CC, HQ in water samples with good selectivity and high sensitivity. Our study contributes to green synthesis of metal-based nanomaterials with multi-enzyme mimicking activities and uncovers new usage of nanozyme in discriminating of environmental pollutants.

Catalytic patch with redox Cr/CeO2 nanozyme of noninvasive intervention for brain trauma

Traumatic brain injury (TBI) is a sudden injury to the brain, accompanied by the production of large amounts of reactive oxygen and nitrogen species (RONS) and acute neuroinflammation responses. Although traditional pharmacotherapy can effectively decrease the immune response of neuron cells via scavenging free radicals, it always involves in short reaction time as well as rigorous clinical trial. Therefore, a noninvasive topical treatment method that effectively eliminates free radicals still needs further investigation.Methods: In this study, a type of catalytic patch based on nanozymes with the excellent multienzyme-like activity is designed for noninvasive treatment of TBI. The enzyme-like activity, free radical scavenging ability and therapeutic efficacy of the designed catalytic patch were assessed in vitro and in vivo. The structural composition was characterized by the X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy technology.Results: Herein, the prepared Cr-doped CeO2 (Cr/CeO2) nanozyme increases the reduced Ce3+ states, resulting in its enzyme-like activity 3-5 times higher than undoped CeO2. Furthermore, Cr/CeO2 nanozyme can improve the survival rate of LPS induced neuron cells via decreasing excessive RONS. The in vivo experiments show the Cr/CeO2 nanozyme can promote wound healing and reduce neuroinflammation of mice following brain trauma. The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases.Conclusions: The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases.

Correction to "Ultrasmall RuO2 Nanozyme Exhibiting Multienzyme-like Activity for the Prevention of Acute Kidney Injury".

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to “Ultrasmall RuO2 Nanozyme Exhibiting Multienzyme-like Activity for the Prevention of Acute Kidney Injury”Zhou LiuZhou LiuMore by Zhou Liu, Lina XieLina XieMore by Lina Xie, Kangqiang QiuKangqiang QiuMore by Kangqiang Qiu, Xinxing LiaoXinxing LiaoMore by Xinxing Liao, Thomas W. ReesThomas W. ReesMore by Thomas W. Rees, Zizhuo Zhao*Zizhuo ZhaoMore by Zizhuo Zhao, Liangnian JiLiangnian JiMore by Liangnian Ji, and Hui Chao*Hui ChaoMore by Hui Chaohttp://orcid.org/0000-0003-4153-5303Cite this: ACS Appl. Mater. Interfaces 2020, 12, 34, 38813Publication Date (Web):August 13, 2020Publication History Published online13 August 2020Published inissue 26 August 2020https://doi.org/10.1021/acsami.0c12821Copyright © 2020 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views889Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (488 KB) Get e-Alerts Get e-Alerts

An Ultrasmall RuO2 Nanozyme Exhibiting Multienzyme-like Activity for the Prevention of Acute Kidney Injury.

Oxidative stress induced by reactive oxygen species (ROS) is one of the major pathological mechanisms of acute kidney injury (AKI). Inorganic nanomaterial-mediated antioxidant therapy is considered a promising method for the prevention of AKI; however, currently available antioxidants for AKI exhibit limited clinical efficacy due to the glomerular filtration threshold (∼6 nm). To address this issue, we developed ultrasmall RuO2 nanoparticles (RuO2NPs) (average size ≈ 2 nm). The NPs show excellent antioxidant activity and low biological toxicity. In addition, they can pass through the glomerulus to be excreted. These properties in combination make the ultrasmall RuO2NPs promising as a nanozyme for the prevention of AKI. The NP catalytic properties mimic the activity of catalase, peroxidase, superoxide dismutase, and glutathione peroxidase. The nanozyme can be efficiently and rapidly absorbed by human embryonic kidney cells while significantly reducing ROS-induced apoptosis by eliminating excess ROS. After intravenous injection, the ultrasmall RuO2NPs significantly inhibit the development of AKI in mice. In vivo toxicity experiments demonstrate the biosafety of the NPs after long-term preventing. The multienzyme-like activity and biocompatibility of the ultrasmall RuO2NPs makes them of great interest for applications in the fields of biomedicine and biocatalysis.

Hyaluronic Acid-Modified Au-Ag Alloy Nanoparticles for Radiation/Nanozyme/Ag+ Multimodal Synergistically Enhanced Cancer Therapy.

Gold nanoparticles (AuNPs) have been widely documented as tumor radiosensitizers via enhanced energy deposition of ionizing radiation. However, the sensitization efficiency of AuNPs is still far from satisfactory owing to the irradiation on nontarget tissues and the tumor radio-resistance. To address these issues, we report herein the rational design and development of hyaluronic acid-modified Au-Ag alloy nanoparticles (Au-Ag@HA NPs) with effective tumor radiosensitization by receptor mediated tumor targeting as well as microenvironment-activated hydroxyl radicals (•OH) generation. In our work, Au-Ag@HA NPs were synthesized by the coreduction of HAuCl4 and AgNO3 in the presence of trisodium citrate, followed by surface modification of HA to the Au-Ag alloy NPs. HA modification affords the alloy NPs with specific targeting to 4T1 breast cancer cells overexpressing CD44 receptor, while the introduction of Ag atom imparts the alloy NPs with superior multienzyme-like activities to the monometallic AuNPs for efficient tumor catalytic therapy. More importantly, the ionizing radiation and peroxidase-like activity of Au-Ag@HA NPs boost the production of •OH and the release of toxic Ag+ in the tumor sites, thereby leading to effective tumor therapeutic outcome. This work provides a promising treatment paradigm for radiation/nanozyme/Ag+ combined therapy against cancer and will advance the design and development of multifunctional nanoplatforms for synergetically enhanced tumor therapy.

Ultra-small platinum nanoparticles on gold nanorods induced intracellular ROS fluctuation to drive megakaryocytic differentiation of leukemia cells.

Chronic myeloid leukemia (CML) is a kind of hematological malignancy featured with retarded differentiation that is highly linked to the level of intracellular reactive oxygen species (ROS). In this work, ultra-small platinum nanoparticles deposited on gold nanorods (Au@Pt) were synthesized and applied on the CML cells. It was shown that Au@Pt had multienzyme-like activities that induced a fluctuation of the intracellular ROS level over the incubation time, depending on their temporal locations in the cells. The ROS fluctuation triggered cellular autophagy and enhanced the level of autophagic protein Beclin-1, which caused the degradation of fusion protein BCR-ABL, the key factor of retarded differentiation and led to the downregulation of phosphorylation of PI3K and AKT. These interactions together broke retarded differentiation and drove the CML cells to differentiate towards megakaryocytes, which is of great significance in enhancing leukemic cell apoptosis. Therefore, Au@Pt exhibited a novel function and promising therapeutic potential for the CML treatment.

Cerium oxide based nanozymes: Redox phenomenon at biointerfaces.

Cerium oxide nanoparticles (nanoceria) are known to exhibit enzymelike activity, such as biological catalase, oxidase, superoxide dismutase, and peroxidase enzymelike activities. Catalytically active nanoceria offer several advantages over natural enzymes, such as controlled synthesis at low cost, tunable catalytic activities, as well as high stability against stringent physiological conditions. Exploiting these properties, several biomedical applications, such as biosensing, immunoassay, drug delivery, radiation protection, and tissue engineering, have been maneuvered. This review article provides a comprehensive summary of reported biological enzymelike activities of nanoceria and the possible mechanism of catalysis. It is also discussed that what physicochemical properties (surface charge, size, surface chemistry, and enzymelike activity) of nanoceria are altered when exposed to biologically relevant buffers and even in the mammalian cell cytoplasm. Based on various reports provided in the literature, these important issues need to be addressed. It has also been deliberated that in mammalian cells variations in properties of nanoceria observed are due to the intrinsic catalytic activity or as a result of downstream effects that could have emerged after the particles have interacted with biologic/environmental components. Such studies could be helpful in providing a better understanding the nanoceria's multienzyme-like activities and potential applications in the biomedical fields with special reference to damaging effects of free radicals in biological systems.

Prussian blue nanoparticles possess potential anti-inflammatory properties via scavenging reactive oxygen species

Iron-based nanomaterials are thought to be cytotoxic in recent researches due to the mechanism that they can produce hydroxyl radical (•OH) in cells via Fenton reaction. However, we found Prussian blue nanoparticles (PBNPs) possess reactive oxygen species (ROS) scavenging ability due to their peroxidase (POD), catalase (CAT), super-oxide dismutase (SOD)-like activities and affinity for •OH. We theorized the multienzyme-like activities of PBNPs were caused by their abundant redox potentials in different forms: Prussian White (PW), Prussian blue (PB), Berlin Green (BG) and Prussian Yellow (PY), what makes them admirable electron transporters. The reported PBNPs show anti-inflammation ability in lipopolysaccharide (LPS)-induced cell and animal inflammation research endeavors.

Prussian Blue Nanoparticles as Multienzyme Mimetics and Reactive Oxygen Species Scavengers

The generation of reactive oxygen species (ROS) is an important mechanism of nanomaterial toxicity. We found that Prussian blue nanoparticles (PBNPs) can effectively scavenge ROS via multienzyme-like activity including peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD) activity. Instead of producing hydroxyl radicals (•OH) through the Fenton reaction, PBNPs were shown to be POD mimetics that can inhibit •OH generation. We theorized for the first time that the multienzyme-like activities of PBNPs were likely caused by the abundant redox potentials of their different forms, making them efficient electron transporters. To study the ROS scavenging ability of PBNPs, a series of in vitro ROS-generating models was established using chemicals, UV irradiation, oxidized low-density lipoprotein, high glucose contents, and oxygen glucose deprivation and reperfusion. To demonstrate the ROS scavenging ability of PBNPs, an in vivo inflammation model was established using lipoproteins in Institute for Cancer Research (ICR) mice. The results indicated that PBNPs hold great potential for inhibiting or relieving injury induced by ROS in these pathological processes.