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Nanomaterials with enzyme-like characteristics (nanozymes):next-generation artificial enzymes †
Hui Wei*z and Erkang Wang*
Over the past few decades,researchers have established artificial enzymes as highly stable and low-cost
alternatives to natural enzymes in a wide range of applications.A variety of materials including cyclodextrins,metal complexes,porphyrins,polymers,dendrimers and biomolecules have been extensively explored to mimic the structures and functions of naturally occurring enzymes.Recently,some nanomaterials have been found to exhibit unexpected enzyme-like activities,and great advances have been made in this area due to the tremendous progress in nano-research and the unique characteristics of nanomaterials.To highlight the progress in the field of nanomaterial-based artificial enzymes (nanozymes),this review discusses various nanomaterials that have been explored to mimic different kinds of enzymes.We cover their kinetics,mechanisms and applications in numerous fields,from
biosensing and immunoassays,to stem cell growth and pollutant removal.We also summarize several approaches to tune the activities of nanozymes.Finally,we make comparisons between nanozymes and other catalytic materials (other artificial enzymes,natural enzymes,organic catalysts and nanomaterial-based catalysts)and address the current challenges and future directions (302references).
1.Introduction
Artificial enzymes,the term coined by Ronald Breslow for enzyme mimics,1is a very important and exciting branch of biomimetic chemistry which is inspired by nature and aims to imitate the essential and general principles of natural enzymes using alter-native materials.2,3Over the past few decades,researchers have established artificial enzymes as highly stable and low-cost alter-natives to natural enzymes in a wide range of applications.Cyclodextrins,metal complexes,porphyrins,polymers,supra-molecules and biomolecules (such as nucleic acids,catalytic antibodies and proteins)have been extensively explored to mimic the structures and functions of natural enzymes through various approaches.1–17To date,remarkable progress has been made in the field of artificial enzymes (Fig.1),and several monographs and numerous excellent reviews have been published.2–4,18–34
Recently,some nanomaterials,such as fullerene derivatives,gold nanoparticles,rare earth nanoparticles and ferromagnetic nanoparticles,have been found to exhibit unexpected enzyme-like
activity.35–48Since then,considerable advances have been made in this area due to the tremendous progress in nano-research and the unique characteristics of nanomaterials.49–53These nanomaterial-
based artificial enzymes (nanozymes)have already found wide applications in numerous fields,including biosensing,immunoassays,cancer diagnostics and therapy,neuroprotection,stem cell growth,and pollutant removal.The term ‘‘nanozymes’’was initially coined by Scrimin,Pasquato and co-workers to describe their thiol monolayer protected gold clusters with outstanding ribonuclease-like activity.39Here,we adopt the term and extend it to nanomaterials with enzyme-like activities.Although the progress and achievements of classic artificial enzymes have been thoroughly reviewed in the litera-ture,no comprehensive review has been devoted to nano-zymes.51–63To highlight the significant progress of nanozyme research,this review discusses various nanomaterials that mimic natural enzymes and their mechanisms,kinetics and numerous applications.Different approaches to tune the activities of nano-zymes are summarized.We also compare nanozymes to other catalytic materials (such as other artificial enzymes,natural enzymes,organic catalysts and nanomaterial-based catalysts).Finally,we discuss the current challenges facing nanozyme technologies and future directions to realize their great potential.Note:although nanozymes include artificial hydrolytic enzymes and others,the current review mainly focuses on redox-based nanozymes,the intrinsic enzyme-like activities of which are from
State Key Laboratory of Electroanalytical Chemistry,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun,Jilin 130022,China.E-mail:weihui@nju.edu,ekwang@ciac.jl
†Electronic supplementary information (ESI)available:See DOI:10.1039/c3cs35486e
‡Current address:Department of Biomedical Engineering,College of Engineer-ing and Applied Sciences,Nanjing University,Nanjing,Jiangsu,210093,China.
Received 28th November 2012DOI:10.1039/c3cs35486e
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the nanomaterials cores instead of the functional groups present on the protecting shells.
Readers are referred to the monographs and reviews for more comprehensive information regarding other artificial enzymes rather than nanozymes (note:due to the space limit,only a small number of references are cited).2–4,17–32,64–67
2.Nanomaterials as nanozymes to mimic natural enzymes
At first glance,it seems counterintuitive to imitate natural enzymes with nanomaterials since they are so different in many ways.For example,most natural enzymes,which are
proteins,
Fig.1A brief timeline for the development of artificial enzymes (natural enzymes are also listed for comparison)(see Table S1,ESI†for related
references).
Hui Wei
Hui Wei is a Professor in College of Engineering and Applied Sciences at Nanjing University.He joined Nanjing University after postdoctoral training with Professors Yi Lu and Shuming Nie,respectively.He received his BS degree from Nanjing University in 2003,where he carried out undergraduate research with Professor Xinghua Xia.In the same year he joined Professor Erkang Wang’s group at Changchun Institute of Applied
Chemistry,Chinese Academy of Sciences,and received his PhD degree in 2008.He has published over 30papers in peer-reviewed international journals.His work has been cited more than 1500times with an H-index of 24.His research interests are focused on functional nanomaterials and new methodology for analytical and biomedical
applications.
Erkang Wang
Erkang Wang is a Professor of Chemistry at Changchun Institute of Applied Chemistry,Chinese Academy of Sciences.He is Academicians of the Chinese Academy of Sciences and the Third World Academy of Sciences.He obtained his BS degree from University of Shanghai in 1952and his PhD degree from Czechoslovak Academy of Sciences in 1959under the direction of Professor J.Heyrovsky (Nobel Laureate).He
has published over 690papers in peer-reviewed journals.His work has been cited more than 15000times with an H-index of 62.His research interests lie in the fields of nanomaterials/nanotechnology,biosensors,electrochemistry and electrochemiluminescence.
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have exact amino acid sequences and thus well-defined tertiary structures.On the other hand,most nanomaterials are not atomically uniform due to size and shape variations.68Proteins are also considered as soft materials while nanomaterials can be hard with crystalline cores.68However,they share certain similarities,such as overall size,shape and surface charge,which enable nanomaterials to mimic natural enzymes.68In this section,we will survey various nanomaterials that can mimic natural enzymes.2.1
Cerium oxide-based nanomaterials
Cerium oxide (ceria)is well known for its highly catalytic performance in various applications due to the presence of mixed valence states of Ce 3+and Ce 4+,and the presence of oxygen vacancies.51,53,69Oxygen vacancies compensate the reduction of positive charge by Ce 3+and thus stabilize the chemically active Ce 3+oxidation state.The redox couple can switch between each state in a CeO 22CeO 2Àx +x /2O 2(Ce 4+2Ce 3+)recycle process,which is the key to the catalytic activity.51,53Moreover,nanoceria has dominant Ce 3+and oxygen vacancies on its surface due to a lar
ge surface-to-volume ratio.Early studies have shown that cerium complexes have many biological applications.For example,cerium(III )nitrate decreased superoxide content and thus promoted the germination of aged rice seed.70Thus,it was reasonable to investigate the superoxide oxidase (SOD)mimetic activity of nanoceria for catalytic removal of superoxide radicals.The seminal study by Seal et al.showed that vacancy-engineered nanoceria indeed protected normal cells but not tumor cells from radiation-induced damage (Fig.2).41The protective role of the nanoceria was attributed to the elimination of radiation-induced free radicals,which were hypothesized to occur through catalyza-tion via a Ce 3+-Ce 4+-Ce 3+regeneration process.The differ-ential protecting capabilities in normal cells vs .tumor cells might be due to the fact that chromatin in tumors was more loosely packed and thus exposed more bases for free-radical attack.41Following this early work,numerous studies have confirmed the enzyme (including SOD,catalase,oxidase,etc.)mimetic properties
of nanoceria and have shown promising biomedical applications for scavenging radicals both in vitro and in vivo .43,51,53,71–108Here,we discuss the enzyme mimetic properties of nanoceria and their applications.
2.1.1Nanoceria as SOD mimics.SOD catalyzes the dismuta-tion of superoxide anions into hydrogen peroxide and molecular oxygen (Scheme 1).Superoxide anion,one of the reactive oxygen species,has
been known to cause tissue injury and associated inflammation.Previous research has revealed that SOD play protective roles in the removal of superoxide anions.Due to the limits of native SOD (such as short term stability and high cost),significant efforts have been made to develop SOD mimics.23,59,64For example,a manganese-containing biscyclo-hexylpyridine complex,M40403,has been developed for this purpose.64Inspired by the work from Seal and co-workers,recent studies have showed that nanoceria exhibits interesting and promising SOD activity.43,71,73,76,80,88,91,102
No direct evidence was presented to support the redox regeneration mechanism in the early study.41In a later study,Seal et al.performed a competitive assay against cytochrome c ,which indicated the SOD mimicking activity of the nanoceria.73The superoxide anion elimination capability of the nanoceria was also confirmed by electron paramagnetic resonance (EPR)measurements.76The results showed that nanoceria with a higher ratio of Ce 3+/Ce 4+has better activity.73They also observed the formation of hydrogen peroxide,which is one of the products of the SOD catalyzing reaction.The kinetics measure-ment showed that the nanoceria with a size of 3–5nm was more efficient as a SOD mimic than a native CuZn SOD (with rate constants of 3.6Â109M –1s –1and (1.3–2.8)Â109M –1s –1,respectively).A dismutation mechanism similar to Fe-and Mn-SOD was proposed (Fig.3a).73An alternative mechanism was also proposed as shown in Fig.3b.53None of them clearly in
volved the auto-regeneration process of Ce 3+on nanoceria,though the second mechanism indicated that nanoceria with a higher ratio of Ce 3+/Ce 4+should have higher activity.If an auto-regeneration process indeed occurred,the ratio of H 2O 2to O 2would be larger than 1.This could be tested and verified experimentally in the future.Computational studies would also help to clarify the detailed mechanism when combined with further experimental results.Though initial studies suggested that nanoceria could also eliminate hydroxyl radicals,43,72later EPR measurements demon-strated that nanoceria does not have such hydroxyl radical elim-ination capability.76This also suggested that nanoceria has some specificity towards superoxide radicals dismutation.
Applications.SOD mimics play important roles in many redox-active processes,such as scavenging reactive oxygen species,acting as anti-inflammatory and anti-oxidation agents,and promoting stem cell growth.Below,several selected examples are discussed to show the wide and promising applications of nanoceria based SOD
mimics.
Fig.2Nanoceria with SOD mimicking activity could prevent normal human breast cell line (CRL8798)but not a human breast tumor cell line (MCF-7)from radiation induced damage.Reprinted with permission from ref.41.Copyright (2005)American Chemical
Society.
Scheme 1The reaction catalyzed by SOD.
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(a)Anti-inflammatory effects.Similar to native SOD,nano-ceria-based nanozymes exhibit anti-inflammatory effects due to the presence of mixed valence and oxygen defects,rendering them as highly efficient catalysts.Hirst and co-workers reported the anti-inflammatory properties of nanoceria.84Using J774A.1murine macrophage cells as a model,they demonstrated that the nanoceria were benign and were internalized by the cells.Chemiluminescent and fluorescent measurements demon-strated that the nanoceria was able to decrease ROS production in J774A.1cells.They further showed that nanoceria inhibited the production of the free radical nitric oxide,a critical med-iator of inflammation when over-expressed.They also claimed that the nanoparticles did not cause any in vivo lesions in mice when different doses were administered intravenously,but did not further investigate the in vivo activity of the nanozymes.(b)Antioxidants.Nanoceria-based SOD mimics have also been investigated as antioxidants.The antioxidant effects and the biological antioxidant mechanisms of nanoceria were examined by gradual doping of Sm 3+.91Since the doping decreased the Ce 3+concentration without affecting oxygen vacancies,the study confirmed that the Ce 3+/Ce 4+redox reactions were responsible for the nanozym
es’outstanding biological activ-ities.91When encapsulated within a ferritin cage,Liu et al.showed that the ROS-scavenging activity of    4.5nm nanoceria was enhanced.99The presence of a ferritin shell also facilitated cellular uptake and improved their biocompatibility.A recent study showed that nanoceria was able to protect cardiac progenitor cells (CPCs),a promising cell source for cardiac regeneration,from hydrogen peroxide-induced cytotoxicity for one week.100The observed protective effects was attributed to the nanozyme’s self-regenerating antioxidant mechanism involving the Ce 3+/Ce 4+redox cycles.
(c)Promotion of stem cell growth.Polymeric biomaterials have been extensively used in tissue engineering (such as in directing the growth of stem cells)because of their unique properties.Hybrid materials formed by incorporating inorganic materials into a polymeric matrix have even more promising advantages,such as novel functionalities,enhanced biocom-patibility and improved mechanical and chemical properties.In their interesting study,Mandoli and co-workers showed that when nanoceria was fabricated together with PLGA scaffolds,the as-prepared hybrids exhibited enhanced mechanical prop-erties.87They further cast the hybrids onto pre-patterned molds and demonstrated that the composite scaffold could align murine-derived cardiac and mesenchymal stem cells growth with enhanced bioactivity and better adhesion (Fig.4).They then elucidated the potential m
echanism by comparing the nanoceria composites to PLGA films without nanoceria and PLGA films with nanostructured TiO 2.Though nanostructured TiO 2also induced directional cell growth,the cell proliferative activity was lower than the activity observed for nanoceria-loaded PLGA.Since the Ce 3+/Ce 4+redox pair of nanoceria is recyclable while the Ti 3+/Ti 4+redox pair of TiO 2is not,the improved performance of the nanoceria hybrids was attributed to the nanoceria’s anti-oxidation properties.
(d)Neuroprotection.Nanoceria as a SOD mimic also exhibited neuroprotective activity.43,72,92In Chen and co-workers’semi-nal study,they showed that the pretreatment of cultured retinal neuron cells with nanoceria eliminated the accumulation of hydrogen peroxide-induced reactive oxygen intermediates.43More importantly,their animal studies have firmly demon-strated that the nanozymes protected rat retina photoreceptor cells from light-induced degeneration after intravitreal injection (Fig.5).Surprisingly,the nanozymes still exhibited protective activity towards photoreceptor cells even when administrated after the light exposure.Again,the reactive oxygen intermediate-scavenging activity was attributed to the switchable feature of the Ce 3+/Ce 4+redox pair.Later studies showed that the nanozymes’neuroprotective activity could be realized in other systems,
such
Fig.3Proposed mechanisms of nanoceria based SOD mimic:(a)reprinted with permission from ref.73;copyright (2007)Royal Society of Chemistry;(b)reprinted with permission from ref.53;copyright (2011)Royal Society of
Chemistry.
Fig.4Stem cell aligned growth induced by nanoceria in PLGA scaffolds.Reprinted with permission from ref.87.Copyright (2010)John Wiley and Sons.
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