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REVIEWNationalScienceReview9:nwac124,2022https://doi.org/10.1093/nsr/nwac124Advanceaccesspublication27June2022MATERIALSSCIENCENanotechnologyforthemanagementofCOVID-19duringthepandemicandinthepost-pandemiceraChunXu1,2,∗,†,ChangLei3,†,SepantaHosseinpour1,2,SasoIvanovski1,2,LaurenceJ.Walsh1andAliKhademhosseini4,∗1SchoolofDentistry,TheUniversityofQueensland,Brisbane4006,Australia;2CentreforOrofacialRegeneration,ReconstructionandRehabilitation(COR3),SchoolofDentistry,TheUniversityofQueensland,Brisbane4006,Australia;3AustralianInstituteforBioengineeringandNanotechnology,TheUniversityofQueensland,StLucia4072,Australiaand4TerasakiInstituteforBiomedicalInnovation,LosAngeles,CA90064,USA∗Correspondingauthors.E-mails:[email protected];[email protected]†Equallycontributedtothiswork.Received14March2022;Revised5June2022;Accepted8June2022ABSTRACTFollowingtheglobalCOVID-19pandemic,nanotechnologyhasbeenattheforefrontofresearcheffortsandenablesthefastdevelopmentofdiagnostictools,vaccinesandantiviraltreatmentforthisnovelvirus(SARS-CoV-2).Inthisreview,wefirstsummarizenanotechnologywithregardtothedetectionofSARS-CoV-2,includingnanoparticle-basedtechniquessuchasrapidantigentesting,andnanopore-basedsequencingandsensingtechniques.ThenweinvestigatenanotechnologyasitappliestothedevelopmentofCOVID-19vaccinesandanti-SARS-CoV-2nanomaterials.Wealsohighlightnanotechnologyforthepost-pandemicera,byprovidingtoolsforthebattlewithSARS-CoV-2variantsandforenhancingtheglobaldistributionofvaccines.NanotechnologynotonlycontributestothemanagementoftheongoingCOVID-19pandemicbutalsoprovidesplatformsfortheprevention,rapiddiagnosis,vaccinesandantiviraldrugsofpossiblefuturevirusoutbreaks.Keywords:COVID-19,nanotechnology,SARS-CoV-2,diagnosis,vaccinesINTRODUCTIONThecurrentglobalcoronavirusdisease2019(COVID-19)pandemiccausedbythenovelcoronavirus(severeacuterespiratorysyndromecoronavirus2,SARS-CoV-2)thatbeganin2019hasgreatlychangedtheworld.AccordingtotheWorldHealthOrganization(WHO),thenumberofconfirmedcaseshasexceeded418million,withover5.8milliondeathsacrossover200countriesandterritories(asofFebruary2022)[1].InthebattleagainstsurgesininfectionwithSARS-CoV-2,nanotechnologyhasbeenatthefore-front,enablingtherapiddevelopmentofdiag-nosticmethods,vaccinesandantiviralmedicines[2,3].Nanoparticle-baseddetectionmethodssuchaslateralflowassays(LFAs)forSARS-CoV-2anti-genshavebeenusedforrapidantigentesting.Nanopore-basedsequencingplatformshavepro-videdalternativesformoleculargeneticanalysesus-ingthereal-timereversetranscription-polymerasechainreaction(RT-PCR)[4].Antiviralnanomateri-alsarealsoemergingaspandemiccountermeasures[5].NanoparticleshavebeenprominentinmRNAvaccinedesigns,wherelipidnanoparticleshavebeenusedtodelivermRNAinthevaccinesfromPfizerandModerna,withover10billiondoseshavingbeenadministeredwithinthefirsttwoyearsofthepandemic.Atthegloballevel,thestrugglewithcontain-ingtheviruscontinues,asmorecontagiousvariantshaveemerged,suchastheDelta(B.1.617.2)andOmicronstrains(B.1.1.529).TheOmicronvariantspreadatunprecedentedspeed,withover125mil-lionnewinfectionseachdayduringJanuary2022,whichwas10timesfasterthanDelta.Withris-inglevelsofCOVID-19vaccination,includingtheuseofboosterthirdvaccinedoses,combinedwithhighlevelsofinfection-acquiredimmunity,someobservershavepredictedtheendofthepandemicin2022,butwithSARS-CoV-2continuingasafifthendemichumancoronavirusinglobalcirculationfortheforeseeablefuture[6].Thus,theworld’spopula-tionwillbelivingwiththevirusinthepost-pandemicera.Nanotechnologywilllikelycontinuetocon-tributetothemanagementofCOVID-19-relatedissues,includingthemultiplehealthproblemsofCTheAuthor(s)2022.PublishedbyOxfordUniversityPressonbehalfofChinaSciencePublishing&MediaLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(https://creativecommons.org/licenses/by/4.0/),whichpermitsunrestrictedreuse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124‘longhaulCOVID’thatdevelopmorethanthreemonthsaftertheacuteinfection.Inthepost-pandemicera,theapplicationofnanotechnologyisimportantintermsofglobalpreparationforfutureviralpandemics.Inthisreview,wediscusstheroleofnanotechnologyinthediagnosisandtreatmentofCOVID-19anditsroleinthepost-pandemicera.Wediscussnanotechnologyasappliedtothede-tectionofSARS-CoV-2,vaccinedevelopmentandthedevelopmentofantiviralmedicines.Fromthere,wediscusstheroleofnanotechnologyinthepost-pandemiceraandhighlightnanoscaleinformationinthebattlewithSARS-CoV-2variantsandtheglobaldistributionofvaccines.Finally,wepresentourperspectivesonnanotechnologyfortheman-agementofviraldiseases,consideringthelessonslearntthatwillinformthemanagementoffuturepandemics,intermsofnanotechnologyforpreven-tion,diagnosisandtreatment.NANOTECHNOLOGYFORDETECTIONOFSARS-COV-2Rapididentificationofinfectedpatientsisessentialforeffectiveisolationandquarantineprotocols,tohelplimitthespreadofinfection.Withinweeksaf-terthefirstpublishedreportofCOVID-19,thefullsequenceoftheSARS-CoV-2genomehadbeende-termined,anditwassharedglobally,informingthedevelopmentofvaccinesandmedicines.NanoscalefeaturesoftheSARS-CoV-2viruswerecharacter-izedusingcryo-electronmicroscopy[7,8].Theseanalysesrevealedthatforviralentryintohumancells,theviralspike(S)proteinbindstoangiotensin-convertingenzyme2(ACE2),andthisisfollowedbymembranefusionoftheviralenvelopeandthehostcellmembrane.Traditionalimmunoassaysandnucleic-acid-amplificationtestsusingRT-PCRhavebeendeployedtomeasureantibodylevelsandviralload,toassesspastinfectionandcurrentinfection,respectively.Duetohighlevelsofdemandfortheselaboratory-basedtests,greateremphasishasbeenplacedonpoint-of-careandself-administeredrapidantigentesting(RAT).Suchtestinghasallowedtimelyidentificationofasymptomaticcases,inworkplaces,inthegeneralcommunityandincriticalservicessuchashealthcare.RATusesnanoparticles,particularlycolloidalgold(Fig.1a),forgeneratingavisualchange.Fornucleicaciddetection,inadditiontotraditionalRT-PCR,nanopore-basedsequencingtechniquesforvirusdetectioncanalsobeused(Fig.1b).Nanomaterial-basedsensorsforvirusdetectionhavealsobeendeveloped(Fig.1c)[9].Nanoparticle-basedtechniquesfordetectionofSARS-CoV-2Arangeofnanoparticles,includingcolloidalgoldnanoparticles,quantumdots(QDs),rareearthnanoparticles,magneticnanoparticles,carbonnan-otubesandhybridnanoparticlessuchasQD-dopedmesoporoussilicananoparticles,canbeusedinimmunoassaystodetectvarioustargets(Fig.1a)[10,11].Thetestscanbeusedwithnasalswabs,throatswabs,sputumsamples,salivasamplesorserum.Thereare49USFDA-approvedantigendi-agnosticdevicesforCOVID-19,asof28May2022,underemergency-useauthorizations.MostofthesediagnosticdevicesareLFAthatusecolloidalgoldnanoparticlesorQDs.Inimmunologicalassays,var-iousnanoparticlesareconjugatedwithantibodies,toeitherrevealavisiblecolourchangeortoallowfluorescent/electrochemical/magneticsignaldetec-tionwhentheconjugatedantibodyhasboundtotheantigen.Colloidal-gold-nanoparticle-basedLFAisthemostcommonone,withtheadvantagesoflowcostandasimpleresult-readingmethod(justbysight;noinstrumentisneeded).Thefluorescence-baseddetectionmethodusesfluorophoressuchasQDsandrareearthnanoparticles(upconver-sionanddownconversionnanoparticles)andof-fershighersensitivityandalowerdetectionlimitcomparedtocolourimetricdetection.QD-basedflu-orescenceassayscanachieveasensitivityatleast10timeshigherthangold-basedonesduetothelowerbackgroundandhigherbrightness.However,specialfluorescereadinginstrumentsareneededfortheresultsreading.Thestrategyofusingasmartphone’scamerawithasimplelightsourcemaypro-videacheapandsimplemethodoffluorescence-baseddetection.MagneticLFAprovidesanotherstrategyforantigenstests,bymeasuringthestrayfieldchangesfromthemagneticnanoparticles.Thesemethodsofferveryhighsensitivityandlowdetectionlimitsduetonoornegligiblebackgroundnoise.However,specialinstrumentssuchasgi-antmagnetoresistancesensorsareneededforthedetectionandarethusnotwidelyusedyet.Re-cently,hybridnanoparticlessuchasQD-loadedmesoporoussilica-basedLFAcouldimprovedetec-tionsensitivityby104timescomparedtocommer-cialcolloidal-gold-basedLFA,andthusmaybeusedforearlydetectionofSARS-CoV-2infection[11].TodetecttheSARS-CoV-2virusinanLFA,theprimarytargetsarethespike(S)protein,thenucleo-capsid(N)proteinofthevirus,theantibodiesortheviralnucleicacid[12].Nproteinantigen-detectingLFAshavesuperiorsensitivityovertraditionalsero-logicalassays,withalimitofdetection(LOD)of3.03ng/mL[13].ToexploitthewidespreadPage2of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac12455 nmNoninfectiousvirusInfectiousvirus55 nmNoninfectiousvirusInfectiousvirusAptamer10NH( )()oFlow directionTest line (T)Control line (C)Anti-antigen antibodyCapture antibodySARS-CoV-2 antigenGold NPsQuantum dotsRare earth NPsCarbon nanotubesHybrid NPsSamplesMagnetic NPs teattttttrttrthhhhhhhhhhhNNPCurrent (pA)Current levels01020Time (s)607080901001.4-2.4 nmAcistrans180 mVbacAFigure1.NanotechnologiesusedfordetectionofSARS-CoV-2.(a)Nanoparticle-basedrapidantigentestsusevariousnanoengineeredapproaches,includingcolloidalgoldnanoparticles,quantumdots,rareearthnanoparticles(upconversionanddownconversionnanoparticles),magneticnanoparticles,carbonnanotubesandhybridnanoparticleswithsizesrangingfromseveraltoseveralhundrednanometers.(b)Thenanopore-basedsequencingtechniqueforvirusdetection.(c)Aporousnanomaterial-basedsensorforvirusdetection.Panelbreproducedwithpermissionfromref.[16].Panelcreproducedwithpermissionfromref.[9].NPs=nanoparticles.availabilityofsmartphonesandthehighqualityofcamerasinsmartphones,anovelassayhasbeende-velopedthatusesanano-enzyme-basedchemilumi-nescenceprocesstodetecttheSprotein.ThisassayhasanLODof0.1ng/mL[14].RAThasbeendeployedonamassivescaleinmanycountries,andthecostpertestislow.Thetrade-offforRATisthatitislesssensitivethanex-pensivelaboratoryassays,byafactorof105timescomparedtoRT-PCR,andby103timesforcellcul-tureassays[15].Onewayofreducingthisperfor-mancegapintermsofsensitivityistousemulti-plexapproachesandfluorescencedetectionforim-munoassays,ratherthansimplevisualreadouts.Nanopore-basedtechniquesfordetectionofSARS-CoV-2NanoporesequencingNanoporesequencingallowsreal-timeanalysisoflongDNAorRNAfragmentsbyusingvoltage-biasednanoscaleporesinamembrane[16,17].Byengineeringproteinnanoporeswitha5nmlongstemandaninsidechanneldiameterthatvariesfrom∼1.4to∼2.4nm[18,19],thepassageofalinear,single-stranded(ss)DNAorRNAmoleculethroughthatporecancausechangesincurrentflow(Fig.1b).Themeasurementofthesechangescanbedecodedusinganalgorithmtogenerateanucleicacidse-quence[16].ThisnanoporesequencingtechniquewasusedtosequencethetranscriptomeofSARS-CoV-2[20],andthenthefull-lengthgenomicRNAofthevirus[21].Bulletal.evaluatedtheanalyticalperformanceofnanoporesequencingforCOVID-19usingthese-quencingdevicesfromOxfordNanoporeTechnolo-gies,andspecimensfromSARS-CoV-2-positivepa-tients(totalnumber:157)andsyntheticRNAcon-trols.Theresultsshowedhighlyaccurateconsensus-levelsequencedetermination,with>99%sensitivityand>99%precisionwithregardtosinglenucleotidevariantsdetectedaboveaminimum∼60-foldcov-eragedepth.ThisstudydemonstratesthevalueofnanoporesequencingforSARS-CoV-2genomeanalysis.However,itwasalsoreportedthatthistech-niquefailedtodetectvariantsatlowread-countfrequenciesaccurately[4].Likewise,Wangetal.combinedreal-timenanoporesequencingwithtar-getedamplificationmethodsforthedetectionofPage3of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124SARS-CoV-2.Within6–10hours,thisapproachcandetectandcategorizeSARS-CoV-2variantsandotherrespiratoryviruses.Clinicaldiagnostictestshavevalidatedthistechnique[22].Nanomaterial-basedsensingSensorsbasedonnanomaterials,especiallyporousnanomaterials,havebeendevelopedforthedirectdetectionofinfectiousvirionsofSARS-CoV-2.DNAaptamers,whichbindintactinfectiousvirions(butnotnon-infectiousvirions),havebeenincorpo-ratedintosolid-statenano-sizedpores.Thisallowsthenanomaterialtostronglybindandconfinethevirus,whichincreasesthesensitivityandlowersthedetectionlimitdownto10000copies/mLforSARS-CoV-2,and1pfu/mLforhumanadenovirus(Fig.1c)[9].Thesecombinedaptamer-nanoporesensorshavebeenusedwithdifferentsampletypes,includingwater,salivaandserum,forthedetectionofbothenvelopedandnon-envelopedviruses.Aptamer-nanoporesensorshavebroadapplicationwhenitcomestodetectingvirusesofpublichealthconcern.Morerecently,metal-organicframework(MOF)-basedsensorshavealsobeendevelopedforSARS-CoV-2detection;theseutilizetheporousstructureandhighsurfaceareaofMOFs.Rabieeandco-authorssynthesizedMOF-5withCoNi2S4(forenhancingtheselectivityofsensors)anddecorateditwiththeporphyrin,H2TMP(asasensitizerforsensors)andachievedadetectionlimitof5nMfortheSARS-CoV-2spikeantigen[23].Thisproof-of-conceptstudydemonstratesthepotentialofusingMOFsaslow-costandefficientsensorsforCOVID-19detection.Inadditiontosingle-plexeddetection,multi-plexedsensingofSARS-CoV-2hasalsobeenre-centlydevelopedbasedonnanomaterials.Gaoandhisgroupdesignedamultiplexedandwire-lesselectrochemicalplatformbasedongrapheneforultra-rapiddetectionofCOVID-19[24,25].Thisnanomaterial-baseddetectiontechniquecantestSARS-CoV-2antigens,antibodiesandC-reactiveproteinstoprovidekeyinformation,includingtheviralinfection,immuneresponseanddiseasesever-ity.TheyalsovalidatedthisplatformusingCOVID-19patientbloodandsalivasamples.NANOTECHNOLOGYANDCOVID-19VACCINESVaccinesremainthemostefficientstrategyforpro-tectionagainstviralinfections.Anappropriatevac-cinewillgenerateantibodiesandmemoryTcellsaswellassensitizedcytotoxiccells.Vaccinedesignin-cludestheidentificationofantigensandadjuvants,aswellasanappropriatedeliverymethodtode-livertheantigensandtriggerproperimmunereac-tions.Nanotechnologyprovidespowerfultoolstodelivertheantigensandpresentthemtotheim-munesystem,andalsoactslikeadjuvantstoelicitstrongerimmuneresponses.Duringthispandemic,thePfizerandModernamRNAvaccinesareusinglipidnanoparticlestodeliverthemRNAthaten-codesforthespikeproteinofSARS-CoV-2,andtheserepresentamilestoneforbothnanotechnol-ogyandthemRNAtechnique.ThemRNAinducestheexpressionofthespikeprotein,triggeringthehostimmuneresponse.BoththePfizerandMod-ernamRNAvaccineshaveareportedefficacyofaround95%forpreventinghospitalizationscausedbylaboratory-confirmedCOVID-19inpeopleaged16orolderwhohavenotbeenpreviouslyinfectedwithSARS-CoV-2[26–28].AsshowninFig.2,themRNAisencapsulatedinlipidnanoparticlescomprisedoflipid,cholesterolandpolyethyleneglycol(PEG).SincenakedmRNAisnotstableandisdegradedreadilybyextracellu-larRNaseenzymes,thelipidnanoparticleprotectsthemRNAduringstorageandafteradministration,andisessentialforvaccineefficacy[29,30].Cellsin-ternalizethenanoparticles,andthemRNAusesthenormalcellularmachineryfortranslationintopro-teins[31].Theselipidnanoparticlesrangeinsizebe-tween80and200nmandaresynthesizedbytheself-assemblyofcationiclipids[32].Inadditiontolipidnanoparticles,othertypesofnanoparticlescanbeusedasnanocarrierstodelivernucleicacidsforvaccines,includingPEG-lipidfunctionalizeddendrimernanoparticles,cationicpeptides,cationicpolymernanoparticlesandpolyethyleneiminenanoparticles[33,34].Nanoparticlescanpossesstheirownimmuno-genicproperties,whichcanstimulateprotectiveimmuneresponsesagainstcoronavirusesandotherviruses[35].Relevantexamplesincludegoldnanoparticles,polymericnanoparticlesandspikeproteinnanoparticles[36].Suchparticlescouldbeadministeredorally,intranasally,andbysubcutaneousorintramuscularinjection.Thesealternativeadministrationmethodsovercometissuebarriersandresultingreateruptakeoftheparticlesintoregionallymphnodes[37,38].Inadditiontoservingasadeliverysystem,nanoparticlescanalsobeusedasadjuvants,toboosttheoverallefficiencyoftheimmuneresponsegen-eratedbyvaccines.Adjuvantsalsoreducethere-quiredantigendose[39].OfthevariousCOVID-19vaccinesindevelopment,10candidatevaccineshaveusedproteinsubunitsincombinationwithananoparticleadjuvant(6atpreclinicaland4atclini-caltestingstage).Page4of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124BNT162b2, 30 µg (N=21,669)Efficacy end-point subgroupPlacebo (N=21,686)VE (95% CI)percentperson-yr (no. at risk)Covid-19 occurrenceAfter dose 1After dose 1 to before dose 2Dose 2 to 7 days after dose 2≥7 days after dose 25039292758221172Surveillance timeNo. of participants4.015 (21,314)person-yr (no. at risk)Surveillance timeNo. of participants3.982 (21,258)82.0 (75.6–86.9)52.4 (29.5–68.4)90.5 (61.0–98.9)94.8 (89.8–97.6)Cumulative incidence (%)2.41.62.01.20.80.40.00119112105989184777063564228493521147Days after dose 1BNT162b2Placebo0.50.40.30.20.10.0018122115963mRNALipidsCholesterolPEG50-100 nmS proteinLipidnanoparticlemRNACELLRibosomeSpike protein(prefusionconformation)bacFigure2.Lipidnanoparticle-basedmRNAvaccinesforCOVID-19.(a)AschematicofthestructureofanmRNAlipidnanopar-ticlevaccine.(b)TheimmuneresponsetothemRNAvaccine.(c)TheefficacyofthePfizermRNAvaccineforCOVID-19(red)versusaplacebo(blue),withthecumulativeincidenceoverfourmonthsafterthefirstinjection.Panelbandcreproducedwithpermissionfromref.[26].Vaccinationusingproteinsubunitsalsoin-volvesnanotechnology.TheseproteinsubunitscomprisevariousexternalstructuralcomponentsoftheSARS-CoV-2virusandarecombinedwithadjuvantstoincreasetheextentofstimulationoftheimmuneresponse[40].Anexampleofnoveldesignistheso-called‘molecularclamp’approach,wheretherelevantsubunitofthevirusisconfinedinanano-sized‘clamp’tokeeptheproteinorpeptideinthecorrectconfiguration[41].Nanoparticlescanbepotentadjuvantsinvac-cinesbecauseoftheirimmune-stimulatingactivity.Theyalsohavemodifiablesurfacechemistry[42,43].Asanexample,aluminananoparticlescoatedwithantigenhavebeenshowntoenhancehumoralandcellularimmuneresponses,becausetheyfacilitateantigencross-presentationtoTcells,andinduceautophagyindendriticcells[44].Likewise,goldnanoparticlescandriveincreasedexpressionofin-flammatorycytokines[45].Table1providesanoverviewofthelandscapeofnanotechnology-basedvaccinesthatareunderpreclinical/clinicalinvesti-gations,basedontheinformationcompiledintheWHOCOVID-19vaccinetracker,asof16May2022[46–49].Intotal,thereare198vaccinesinthepreclinicalstageand156vaccinesunderclinicalin-vestigation.Amongthesevaccines,atleast69havebeendevelopedwithnanotechnology(41preclini-caldevelopmentand28clinicaldevelopment).Sofar,10vaccineshavebeengrantedemergencyuselisting(EUL)bytheWHO(16May2022).NANOTECHNOLOGYFORTHEMANAGEMENTOFCOVID-19Unliketraditionaltherapeutics,whichtendtotar-getaspecificviralspeciesandmaylosetheirefficacyasthevirusaccumulatesmutations,antiviralnano-materialscantargetmanytypesofviruses,becauseoftheircustomizedchemicalandphysicalproper-ties.DNA-basednanostructurescantrapviruses,whilemodifiedpolymerscanserveascellmembranedecoys.Othernanomaterialscandisruptviralen-velopes.Usingsuchapproachesmayofferadvan-tagesinthecontextofcountermeasuresinapan-demic,astheycanbeformulatedrapidly(Fig.3).Nanomaterialswithdirectanti-SARS-CoV-2activityAlthoughSARS-CoV-2canbetransmittedreadilybydropletsandaerosols,contacttransmissionisanimportantadditionalroute,viacontaminatedinani-matesurfacesandpoorhandhygiene[50].ThevirusSARS-CoV-2remainsactiveonarangeofsurfaces,includingglass,metal,woodandplastic,foruptoseveraldays[51].Asaresult,thereisinterestinus-ingantiviralnanomaterials[52,53]andnanoparti-clesthatcancarryantiviralagents[54].AntiviralactivityagainstSARS-CoV-2hasbeenshownforanumberofnanoparticles,includingsilver[55],zincoxide[56],cuprousoxide[57],silica,gold[58]andgrapheneoxidegraftedwithmetalnanoparticlesPage5of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124Table1.Thelandscapeofnano-assistedcoronavirusvaccinecandidatesinclinicalandpre-clinicaltrials.Pre-clinicaldevelopmentVaccineplatformTypeofvaccineDeveloperProteinsubunitNanoparticlevaccineLakePharma,Inc.Spike-basedNanografiNanoTechnology,MiddleEastTechnicalUniversity,AnkaraUniversityRBDproteindeliveredinmannose-conjugatedchitosannanoparticleOhioStateUniversity/KazakhNationalAgrarianUniversityRecombinantprotein,nanoparticles(basedonS-proteinandotherepitopes)SaintPetersburgScientificResearchInstituteofVaccinesandSerumsProteinsubunitnano-formulatedVaxinano,CEA,INRAEPeptideantigensformulatedinlipidnanoparticles(LNPs)IMVInc.NanoparticlevaccineLakePharma,Inc.SsubunitintranasalliposomalformulationwithGLA/3M052adjs.UniversityofVirginiaRNA-basedvaccineLNP-encapsulatedmRNAencodingSMaxPlanckInstituteofColloidsandInterfacesLNP-mRNATranslateBio/SanofiPasteurLNP-mRNACanSinoBiologics/PrecisionNanoSystemsLNP-encapsulatedmRNAcocktailencodingvirus-likeparticle(VLP)FudanUniversity/ShanghaiJiaoTongUniversity/RNACureBiopharmaLNP-encapsulatedmRNAencodingRBDFudanUniversity/ShanghaiJiaoTongUniversity/RNACureBiopharmaLNP-encapsulatedmRNAUniversityofTokyo/Daiichi-SankyoD614GvariantLNP-encapsulatedmRNAGlobeBiotechLtdZIP1642–aself-amplifyingRNA(saRNA)vaccineencapsulatedinanLNP,whichencodesformultipleantigens,includingtheSpike(S)protein.ZiphiusVaccinesandGhentUniversityLNP-mRNACertestBiotecLiposome-encapsulatedmRNABIOCADmRNASelcukUniversitySeveralmRNAcandidatesRNAimmune,Inc.mRNAFBRISRCVBVECTOR,Rospotrebnadzor,KoltsovomRNAChinaCDC/TongjiUniversity/SterminamRNAinanintranasaldeliverysystemeTheRNAmRNAGreenlightBiosciencesmRNAIDIBAPSHospitalClinic,SpainmRNAProvidenceTherapeuticsmRNACellTechPharmedmRNAReNAPCo.DNA-basedvaccinePlasmidDNA,nanostructuredRBDNationalInstituteofChemistry,SloveniaVirus-likeparticleEnvelopedvirus-likeparticle(eVLP)VBIVaccinesInc.SproteinintegratedinHIVVLPsIrsiCaixaAIDSResearch/IRTA-CReSA/BarcelonaSupercomputingCentre/GrifolsVLP+AdjuvantMahidolUniversity/TheGovernmentPharmaceuticalOrganization(GPO)/SirirajHospitalVLPs,lentivirusandbaculovirusvehiclesNavarrabiomed,OncoimmunologygroupVLP,basedonRBDdisplayedonVLPsSaibaGmbHADDomerTMmultiepitopedisplayImophoronLtdandBristolUniversity’sMaxPlanckCentreVLPOSIVAXeVLPARTESBiotechnologyVLPspeptides/wholevirusUniversityofSaoPauloVLPsproducedinBEVSTampereUniversityPlant-derivedVLPShirazUniversityPlasmid-drivenproductionofVLPscontainingS,M,NandEproteinsofSARS-CoV-2ArizonaStateUniversityPage6of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124Table1.Continued.ClinicaldevelopmentVaccineplatformTypeofvaccineDeveloperPhaseVaccineefficiencyRefProteinsubunitSARS-CoV-2rS/MatrixM1-adjuvant(full-lengthrecombinantSARS-CoV-2glycoproteinnanoparticlevaccineadjuvantedwithMatrixM)NVX-CoV2373NovavaxPhase390.4%(CI82.9–94.6)—1dose[46]RecombinantSARS-CoV-2Spikeprotein,aluminiumadjuvanted(NanoCovax)NanogenPharmaceuticalBiotechnologyPhase3Noreportyet-SpFN(spikeferritinnanoparticle)—usesspikeproteinswithaliposomalformulationQS21(ALFQ)adjuvantWalterReedArmyInstituteofResearch(WRAIR)Phase1Noreportyet-T-cell-primingspecificcocktailofcoronaviruspeptidesmountedonagoldnanoparticleEmergexVaccinesPhase1Noreportyet-RNA-basedvaccineCoV2SAMLNPvaccine.Aself-amplifyingmRNALNPplatform+SpikeantigenGlaxoSmithKlinePhase1Noreportyet-mRNA-1273SpikevaxModernaandNationalInstituteofAllergyandInfectiousDiseases(NIAID)Phase493.2%(CI91.0to94.8)—2doses[47]ChulaCov19mRNAvaccineChulalongkornUniversityPhase1/2Noreportyet-PTX-COVID19-B,mRNAvaccineProvidenceTherapeuticsPhase2Noreportyet-ChimpanzeeAdenovirusserotype68(ChAd)andself-amplifyingmRNAvectorsexpressingspikealone,orspikeplusadditionalSARS-CoV-2TcellepitopesGritstoneOncologyPhase1Noreportyet-MRT5500,anmRNAvaccinecandidateSanofiPasteurandTranslateBioPhase2Noreportyet-mRNA-1283.211ModernaTX,Inc.Phase1Noreportyet-mRNACOVID-19vaccineShanghaiEastHospitalandStemirnaTherapeuticsPhase1Noreportyet-ARCT-154mRNAvaccineArcturusTherapeutics,Inc.Phase3Noreportyet-ARCT-165mRNAvaccineArcturusTherapeutics,Inc.Phase1/2Noreportyet-ARCT-021mRNAvaccineArcturusTherapeutics,Inc.Phase1/2Noreportyet-CoronavirusmRNAvaccine(LVRNA009)AIMVaccineandLivernaTherapeuticsPhase2Noreportyet-mRNA-1273.529–BoosterModernaTX,Inc.Phase2/3Noreportyet-CV2CoV,mRNAvaccineCureVacAGPhase1Noreportyet-mRNAvaccine(MIPSCo-mRNA-RBD-1)UniversityofMelbournePhase1Noreportyet-ALyophilizedCOVID-19mRNAvaccineJiangsuRec-BiotechnologyCo.,LtdPhase1Noreportyet-COVID-19mRNAvaccine(SYS6006)CSPCZhongQiPharmaceuticalTechnologyCo.,LtdPhase1Noreportyet-HDT-301:self-replicatingmRNAvaccineformulatedasanLNPSENAICIMATECPhase1Noreportyet-mRNA-1273.351:LNPencapsulatedmRNA-basedvaccinethatencodesforafull-length,prefusionstabilizedSproteinoftheSARS-CoV-2B.1.351variantModernaandNationalInstituteofAllergyandInfectiousDiseases(NIAID)Phase4Noreportyet-LNP-nCoVsaRNAImperialCollegeLondonPhase1Noreportyet(seroconversionatweeksixwasrelatedtodose,rangingfrom8%(3/39;0.1μg)to61%(14/23;10.0μg))[48]Page7of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124Table1.Continued.ClinicaldevelopmentVaccineplatformTypeofvaccineDeveloperPhaseVaccineefficiencyRefBNT162b2(threeLNP-mRNAs),alsoknownas‘Comirnaty’Pfizer/BioNTechandFosunPharmaPhase491.3%(CI89.0–93.2)—2doses[49]LNP-nCOVsaRNA-02vaccine:saRNAencapsulatedinLNPsMRC/UVRIandLSHTMUgandaResearchUnitPhase1Noreportyet-mRNA-1273.211:multivalentboostercandidatecombiningmRNA-1273plusmRNA-1273.351ModernaTX,Inc.Phase2/3Noreportyet-Direct anti-SARS-CoV-2 nanomaterialsNanomaterials for anti-virus drug deliveryNano-engineeredanti-virus surfaceNanoparticles thatbind with virus PDT/PTT Nanoparticles thatdenature virusAnti-virus drugsVarious nano-formulations Deliver totarget cellsIncrease localdrug concentrationSARS-CoV-2SARS-CoV-2NanoparticleIncreaselocalabFigure3.NanotechnologiesforthemanagementofCOVID-19.(a)NanotechnologiesthatfightdirectlyagainstSARS-CoV-2.(b)NanomaterialsasdrugdeliverysystemsagainstSARS-CoV-2.[59].Whenusedtocoatpersonalprotectiveequip-ment,thecombinationofgrapheneoxidewithsil-ver,iron,zincandcoppernanoparticlesimprovesantiviralactivityagainstbothenvelopedandnon-envelopedviruses[59].Giventheimportanceofrespiratoryprotectionviasurgicalrespiratorsforhealthcareworkersdur-ingthepandemic,therehasbeeninterestinusingsuchcompositenanomaterialstocoatthefibreswithintherespirators,orontheoutersurfaceofthefilteringfacepiece.Studyhasdemonstratedthatasilvernanocluster/silicacompositecoatedrespira-torhasaneffectagainstSARS-CoV-2[60],withthepresenceofsilveronfibresconfirmedusingenergydispersivespectroscopy.Suchcoatingscouldbedepositedonpolymeric,metallicandglasssurfaces.Afurthermethodforprovidingasmartantimi-crobialsurfaceistousenanomaterialsthatarelightresponsive[61],toachievedisinfectingactionsafteractivationbyspecificlightwavelengthsthroughphotodynamic,photothermalorphotocatalyticpro-cesses[62,63].Asanexample,ananoscalecoatingofaTiO2photocatalystcaninactivateSARS-CoV-2onthesurfacewhenthereisexposuretolight[61].Nanotechnologycanalsoimproveconventionaldisinfectionmethods,andovercomethelimitationsofcommonbiocides(suchasethanolandsodiumhypochlorite)whenlevelsofsurfaceproteinbiobur-denarehigh[64].Severalapproacheshavebeenintroducedthusfar.Temperature-responsivean-timicrobialnano-coatingscanprovideaprolongeddisinfectingactionbydamagingtheenvelopeofthevirus,inresponsetoappliedheat.NanomaterialscantargetdifferentstagesofSARS-CoV-2viralinfection,suchasfusionoftheviruswiththehostcellmembrane,internalization,viralgenometranscription,translationandreplica-tion.Nanomaterialscanbedesignedtotrapandneu-tralizeSARS-CoV-2withhighefficiency.Forexam-ple,Nieetal.preparedsilicananoparticleswith5to10nmspikes,whichcouldbeinsertedintothesur-faceglycoproteinsoftheinfluenzaAvirusandneu-tralizethem[65].Itislikelythatnanomaterialswithvariouscombinationsofgeometry-matchingtopog-raphyandvirus-bindingsiteswillbedevelopedtotargetSARS-CoV-2aswellasotherviruses.Photothermalantiviralactionscanbeachievedrapidlywhennanoparticlesabsorbnear-infraredlight,andtheresultingheatcausesphotothermaldisinfection[66].Theheatgeneratedwilldenaturepathogensbydamagingenvelopesornucleicacids,orbydenaturingenzymes[67,68].Asanexam-ple,Miyakoetal.havedescribedPEG-carbonnano-hornstaggedbyanantibodythatspecificallytargetstheT7bacteriophage,andbindsthenano-hornstothevirus[53].Irradiationoftheattachednanoparti-cleswithnear-infraredlightfromanNd:YAGlaser(wavelength1064nm)generatesheatandcausesphotothermalinactivationofthebacteriophageef-fect.Suchfunctionalizednanoparticlescanalsobeeffectiveagainstotherviruses,includingHIV,in-fluenzaandSARS-CoV[53].Anotherlight-to-heatconversionplatformwithpowerfulphotothermalPage8of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124disinfectingactionsfeaturessulfonatedmagneticnanoparticlesthathavebeenfunctionalizedwithre-ducedgrapheneoxide.Whenthesenanomaterialswereirradiatedbynear-infraredlaserlight(808nm,1.6W/cm2for10min),thetemperatureroseto55◦C,andthisinactivated99.99%oftype-1herpessimplexvirus[69,70].Afurtherphotothermalprocessusesgoldnanorodsthathavebeenfunctionalizedwithangiotensin-convertingenzyme-2,whichwillbindSARS-CoV-2.Theseparticlescanbeactivatedbynear-infraredlaserirradiation(798nm),toachieveselectiveeliminationofSARS-CoV-2.Thistypeofapproachmayhavevaluewhenpatientsarehospitalizedwithseverepulmonaryinfections[71].Severalmajorconcernswouldneedtobeaddressedbeforesuchclinicalapplicationsofpho-tothermaldisinfectionusingnanoparticlescouldbecontemplated,includingthesafetyandtoxicityofthenanorods,andtheextentofbystanderthermaleffectsonhosttissues.Comparedtotraditionalantiviraldrugs,whichusuallyworkonlyforspecificviruses,nanomateri-alsmayprovidebroadertargetedvirusrangesastheantiviraleffectsaremainlyfromtheirchemi-calandphysicalproperties.Forexample,thespikysilicananoparticlesmayworkforthemutationsofthevirusesaswellasbindtotheglycopro-teinsoftheviruswiththeirnano-topography[65].Nanomaterial-basedstrategiescanprovidefastandcheaptoolsforthemanagementofpandemics,astheycanbedevelopedquicklyandworkagainstalargerangeofvirusesincludingtheirvariants.Nanomaterial-baseddrugdeliveryformanagingSARS-CoV-2infectionNanomaterialscanbeusedassmartcarriersintar-geteddrugdeliverysystemsforantiviralmedicines.Thisleveragestheirdistinctproperties,includinglargesurfacearea,goodbiocompatibilityandeaseofsurfacemodification,allofwhichcanbecus-tomizedduringdesign[72].Usingananotechnol-ogyapproachmayovercomechallengeswithan-tiviralmedicines,suchaspooraqueoussolubilityandlowbioavailability.Itmayalsolowerthedosesneeded,andtherebyreducetoxicity[73,74].Itisalsopossibletousenanoparticlestotargetspecificorgansorcellsthatareinvolvedinthepathophysiol-ogyoftheinfection[75].Inadditiontosmallmolec-ulardrugs,nanoparticlescanalsoeffectivelydeliverotherbioactivemolecules,suchasnucleicacids,pro-teinsandpeptides[76].Varioustypesofnanoparti-cles,includinginorganicnanoparticlessuchasmet-alsandorganicnanoparticlessuchaslipid/liposome,andpolymernanoparticles,havebeenexploredforantiviraldrugdelivery,includinganti-SARS-CoV-2drugs.Inorganicnanoparticleswithsmallsize(1to100nm)suchasmetalnanoparticlescanbesynthe-sized,andthecorrespondingincreaseinthesurfaceareagivesthemahighloadingcapacityforantiviralagents[77].Severalmetalnanoparticleshavebeeninvestigatedforantiviraltherapy.Forexample,seleniumnanoparticleshavebeenusedtodeliverseveralantiviralmedicines,includingribavirin,oseltamivirandzanamivir,topreventapoptosisinducedbyH1N1strainsofthehumaninfluenzavirus[78].Sinceribavirinshowssomeeffectsagainstcoronaviruses,includingSARS-CoVandMERS-CoV[79,80],usingseleniumnanoparticlestocarryribavirinmayalsohavevalueinthetreatmentofSARS-CoV-2infections.Goldnanoparticlescanalsobeusedtodeliverribavirin.ThisapproachhasbeenusedincellcultureswithmeaslesviralinfectionsinanAfricangreenmonkeycellline.Usingthegoldnanoparticlesascarriersimprovestheeffectiveness>5-fold[77].GoldnanoparticleswithlonglinkagesofmercaptoethanesulfonicacidandsulfonateundecanesulfonicacidcanreducemembranefusioncausedbyMERS-CoV[81],mak-ingthisofinterestforSARS-CoV-2treatment.Inadditiontoseleniumandgold,othernanoparticles,includingsilver[82],mesoporoussilica[83,84]andironoxide[85],areprospectivecandidatesfordeliveringantiviralmedicines.Inadditiontometalnanoparticles,cyclodextrin-functionalizedmulti-walledcarbonnanotubeshavebeenusedsuccessfullytotreatherpessimplexviralinfectionthroughthesustainedreleaseofacyclovir[86].Potentialconcernswithmetalnanoparticlesin-cludepoorbiodegradability,withattendantrisksofaccumulationwithinorgans.Lipid-basednanopar-ticlesareattractiveforclinicalusebecauseoftheirgoodbiocompatibilityandbiodegradability.Lipidnanoparticleshavebeenusedasnanocarriersforan-tiviralagents,fortreatinghepatitisCandB,herpessimplexandHIV[87,88].Liposomescanbeusedtodeliverbothhydrophobicandhydrophilicagents.Liposomescontainingacyclovirappliedviathein-tranasalrouteachievegreaterbioavailabilityforthedrug(by60%)comparedwithintravenousadmin-istration[89].Lipidcoatingofothernanoparticles,suchasmesoporoussilicananoparticles,canalsobeundertakentoenhancebiocompatibilityanddura-tionofactionincirculationinvivo,andtoimproveefficiency[90].Polymericnanoparticleshaveattractedinterestbecauseoftheconsiderableflexibilityoftheirdesignandeaseofmodification.Poly(lactic-co-glycolicacid)(PLGA)nanocarriershavebeenshowntoPage9of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124boosttheantiviralactionsofdyphyllineinH1N1in-fluenzainfections,becauseofthesustainedreleaseofthedruginthelung.OptimizedPEGylationofthesenanoparticlespreventedactivationofmacrophagesinthelungforfourweeks[91,92].Suchimmunemodulationeffectsofnanoparticlescouldpoten-tiallybeusefulwhentreatingsevereSARS-CoV-2infections.Polymericnanoparticlescanbeloadedwithcor-ticosteroidsandinhaled.Thisapproachhasbeenusedtotreatasthmaandseverechronicobstruc-tivepulmonarydisease,butcouldalsobeappliedtoSARS-CoV-2infectioninpatientsexperiencingse-vereillnessbecauseofacytokinestorm.Multifunc-tionalpolymericnano-deliverysystemshavecon-siderablepotentialforclinicalapplication,andwithemergencyorexpeditedapprovalcouldbedeployedinthecurrentCOVID-19pandemic[93].Dendrimersaresyntheticnanostructureswithawell-definedbranchingarchitecture.Theyhavegoodbiocompatibility,highsolubilityandareeffectivefordrugencapsulation.Previousworkshaveshowntheirefficiencyasadeliverysysteminthecontextofherpessimplexvirustype-2,HIVandinfluenza[94],anddendrimernanoparticlesaretestedfortheman-agementofSARS-CoV-2[5].NANOTECHNOLOGYFORTHEPOST-PANDEMICERAWithseveralhighlyeffectiveCOVID-19vaccinesdeployedatscaleinmanycountries,animportantquestioniswhethertheuseofnanotechnologyinvaccinesprovidesthenecessaryabilitytorapidlyre-designvaccineswhenconcerningvariantsappearthataremorevirulent.Outlinedbelowarethema-joradvantagesofmRNAdeliveredinlipidnano-carriers.NanoscaleinformationinthebattlewithSARS-CoV-2variantsAsSARS-CoV-2continuestomutate,newvariantsofconcernarebeinggeneratedwithalteredviru-lenceandtransmissibility,resultinginalteredlevelsofprotectionfromexistingvaccines[95].TheOmi-cronvarianthasshownaparticularlyrapidglobalspreadandhasreplacedDeltaasthemostprevalentvariant.Withthehelpofnanotechnology,scientistsdeterminedthenanostructureoftheOmicronspikeproteinincomplexwithhumanACE2at2.45˚Ares-olutionusingCryo-electronmicroscopy[96].ThisstudyalsorevealedthestronginteractionbetweenthemutatedspikeproteinandACEsduetotheform-ingofnewsaltbridgesandhydrogenbonds,whichexplainstherapidspreadandincreaseinantibodyevasionoftheOmicronvariant[96].Thisnanoscaleinformation,andthenewunderstandingbasedonthatnanoscaleinformation,willhelpustolimitthespreadofOmicronandotherpotentialvariants.NanotechnologythatenhancestheglobaldistributionofvaccinesLipidnanoparticlesthatcontainmRNAhavebeenproventobeanefficientmethodfordevelop-ingimmunity.Loworultra-lowtemperaturestor-ageoftheselipidnanoparticle-mRNAvaccinefor-mulations(−20or−80◦C)isnotconvenientforshipping,storageanddistribution,especiallyindevelopingcountriesandinremoteareas.Anewthermostablelipid-nanoparticle-encapsulatedmRNA(mRNA-LNP)vaccine,knownasARCoV,hasbeendevelopedbyamodifiedfabricationpro-cess.ARCoVwasmanufacturedthroughrapidmix-ingofmRNAinanaqueoussolutionandamix-tureoflipidsinethanol,followedbytangentialflowfiltrationtoremoveethanolandconcentratethesolution.ARCoVparticlesaresolidsphereswith-outanaqueouscoreandcanbestoredatroomtemperatureforatleastoneweekwithoutlosingactivity.ThemRNAencodesthereceptor-bindingdomain(RBD)ofSARS-CoV-2.ARCoViscur-rentlybeingevaluatedinphaseoneclinicaltrials[97].Anothernanotechnologyapproachofinterestistheso-called‘nanopatch’.Thiscomprisesarraysofdenselypackedprojectionswithadefinedgeom-etry,whichcanpenetratethroughtheepidermispainlessly.Usingapatchratherthananinjectiondeliversthevaccinestothousandsofantigen-presentingcellsinthedermisandepidermis.Ananopatchvaccinecanbekeptatroomtemperaturewithoutneedingtoberefrigerated.Thisapproachovercomesstorageissuesandalsoavoidstheneedforinjections,tacklingtwobarriersatthesametime.NanotechnologyinpreparationsforthenextpandemicDevelopmentofvaccinesandnanomaterialsforvaccinedeliveryThewidespreaduseoflipidnanoparticlestodelivermRNAvaccineshasincreasedtheawarenessofthisplatform.Therelativeeaseofproductionmakesthisappealingfor‘firstresponse’vaccinesforfuturein-fluenzaorcoronaviruspandemics.Lipidnanoparti-clescouldalsobeusedtodeliverDNAgenethera-piesandCRISPRgene-editingtherapies.Page10of13Downloaded from https://academic.oup.com/nsr/article/9/10/nwac124/6618601 by Jnls Cust Serv on 22 November 2022 NatlSciRev,2022,Vol.9,nwac124Inaddition,otherpolymernanoparticles,protein-basednanoparticles,inorganicnanoparti-clesandexosomesarealsoworthconsideringasvehiclesforfuturevaccines.DevelopmentofantiviralnanomaterialsAsalreadydiscussed,nanoparticlescandeliveran-tiviralmedicinesandcanalso,insomecases,exerttheirownantiviralactionsagainstmultipleviruses.Thismakesthemratherdifferentfromtraditionalan-tiviralagents,whichhavealimitedrangeoftargets.Manyviruses,includingSARS-CoV-2,relyonglyco-proteinsontheirsurfacetobindtoandthenenterhostcells.Nanomaterialscanbedesignedtomimicbindingsites.Asanexample,Zhangetal.prepared‘nanosponges’thatdisplayedthesameproteinre-ceptorsashumancellsandshowedthatthesecanbindtoandneutralizetheSARS-CoV-2virus,pre-ventingitfrominfectingcells.Thisnanospongeap-proachisnotexpectedtobeaffectedbyviralmuta-tions[98].CONCLUSIONSANDOUTLOOKNanotechnologyhasempoweredtheglobalre-sponsetotheCOVID-19pandemic,throughpow-erfultoolsforprevention,diagnosisandtreat-ment.Detectionsystemsbasedonnanoparticlesandnanoporeshaveenabledrapidandinexpensivede-tectionofthevirus,andhaveinformedpublichealthmeasures.OnelessonwehavelearnedduringthisCOVID-19pandemicisthatrapid,large-scalevirusdetectioncangreatlyhelpdiseasecontrolandre-quiresthedevelopmentofvirusdetectionmethodsthataresimpletouse,andhavehighaccuracyandlowcost.Thepowerofnanotechnology-drivende-tectionsuchastheLFAandnanoporesequencecanbefurtherexploredtomanageCOVID-19andotherpotentialvirusdiseases.Duringthispandemic,lipidnanoparticlesforde-liveringmRNAinvaccineshaveplayedamajorroleinpopulation-levelvaccinationstrategies,andwilllikelyplayanincreasingroleinthefuture,bothasaplatformfortherapiddevelopmentofvaccines,andforupdatingvaccinestoaddressviralmutations.Newnanoparticleswithhigherantigen-deliveryef-ficiency,betterstability,especiallythermalstability,andtargetdeliveryaredesiredforvaccines.Thisabil-itytoadjusttothechallengesposedbyarapidlymu-tatingvirusisamajoradvantageofnanotechnology.Nanomaterialsthathavepotentantiviralactionsalsohaveconsiderablepromise.Inthelongterm,nanotechnologywillserveasatechnologicalfoundationforthepreventionandmanagementoffutureviral-infectionpandemics.Appreciationoftheopportunitiesthatnanotech-nologiesofferisnecessaryforeffectivecollaborationbetweenscientists,policymakersandhealthcareprofessionalswhenaddressingthelong-termchal-lengescausedbySARS-CoV-2andpotentialvirusoutbreaks.FUNDINGThisworkwassupportedbyanEarlyCareerFellowshipfromtheNationalHealthandMedicalResearchCouncilofAustraliaandaUQAmplifyFellowshipfromTheUniversityofQueensland.Conflictofintereststatement.Nonedeclared.REFERENCES1.WorldHealthOrganization.CoronavirusDisease(COVID-19)Pandemic.https://www.who.int/emergencies/diseases/novel-coronavirus-2019(7June2022,datelastaccessed).2.TangZM,KongNandZhangXCetal.Amaterials-scienceper-spectiveontacklingCOVID-19.NatRevMater2020;5:847–60.3.TangZM,ZhangXCandShuYQetal.Insightsfromnanotech-nologyinCOVID-19treatment.NanoToday2021;36:101019.4.BullRA,AdikariTNandFergusonJMetal.AnalyticalvalidityofnanoporesequencingforrapidSARS-CoV-2genomeanalysis.NatCommun2020;11:6272.5.PeplowM.NanotechnologyoffersalternativewaystofightCOVID-19pandemicwithantivirals.NatBiotechnol2021;39:1172–4.6.MurrayCJL.COVID-19willcontinuebuttheendofthepandemicisnear.LancetNorthAmEd2022;399:417–9.7.KeZL,OtonJQandQuKetal.StructuresanddistributionsofSARS-CoV-2spikeproteinsonintactvirions.Nature2020;588:498.8.KleinS,CorteseMandWinterSLetal.SARS-CoV-2structureandreplicationcharacterizedbyinsitucryo-electrontomogra-phy.NatCommun2020;11:5885.9.PeinettiAS,LakeRJandCongWetal.DirectdetectionofhumanadenovirusorSARS-CoV-2withabilitytoinforminfec-tivityusingDNAaptamer-nanoporesensors.SciAdv2021;7:eabh2848.10.FaulkWPandTaylorGM.Animmunocolloidmethodfortheelec-tronmicroscope.Immunochemistry1971;8:1081–3.11.GaoF,LiuYandLeiCetal.Theroleofdendriticmesoporoussilicananoparticles’sizeforquantumdotsenrichmentandlat-eralflowimmunoassayperformance.SmallMethods2021;5:2000924.12.ZhouY,WuYandDingLetal.Point-of-careCOVID-19diagnos-ticspoweredbylateralflowassay.TrendsAnalChem2021;145:116452.13.GrantBD,AndersonCEandWillifordJRetal.SARS-CoV-2coro-navirusnucleocapsidantigen-detectinghalf-striplateralflowassaytowardthedevelopmentofpointofcaretestsusingcom-merciallyavailablereagents.AnalChem2020;92:11305–9.14.LiuD,JuCHandHanCetal.NanozymechemiluminescencepapertestforrapidandsensitivedetectionofSARS-CoV-2anti-gen.BiosensBioelectron2021;173:112817.Page11of13Downloaded 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Format for Review Article Outline of the Article Review Please include the following categories in your article review: 1. Full Bibliographic Reference 2. Introduction: Objectives, Article Domain, Audience, Journal and Conceptual/ Empirical Classificatin 3. Brief Summary 4. Results 5. Contributions 6. Foundation 7. Synthesis with Concepts 8. Analysis and Additional Analysis 9. General Critique 10. Further Critique of a Conceptual Article/ an Empirical Article 11. Issues (as listed by the author) 12. Issues (as per your opinion) 13. Relevance/Impact 14. Questions 15. Annotated Bibliography 1. Full Bibliographic Reference State the full bibliographic reference of the article you are reviewing (authors, title, journal name, volume, issue, year, page numbers, etc) 2. Introduction: Objectives, Article domain, Audience, Journal and Conceptual/ Empirical/Review Classification - State the Objective of the Article (goals or purpose), its domain/ topic area. -Identify the intended audience of the article, i.e. what background should reader have; what background material one should be familiar to understand the article? - Is the journal appropriate (or inappropriate) for this article? - Classify whether the article is Conceptual or Empirical or Review 3. Brief Summary Summarize the article very briefly, roughly as under: Paragraph 1: What is the problem being addressed? Paragraph 2: which solution is being proposed? Article Review Template Paragraph 3: what evidence is put forward to support the solution provided (if article is of empirical type, highlight what kind of empirical study was conducted as part of the evidence) 4. Results Briefly summarize the important points (such as observations, conclusions, findings, inferences) and “take home points” in the article. 5. Contributions An article makes a contribution by adding to the knowledge of researchers in a research field. An article can make a contribution to research field in many ways. Does it provide a new way to look at a problem? Does it bring together or “synthesize” several concepts in an insightful way that has not been done before? Does it provide new results/ solutions or identify new issues? Are the issues addressed introduced in a way that their relevance/impact to practice is evident? List the article’s original contribution. Discuss each contribution with due care. 6. Foundation Identify the key pieces of prior research upon which article are built. If the article is entirely new domain, “This article does not build upon any foundation research” may be specified. 7. Synthesis with Concepts Synthesis means analysing a particular topic by comparing and contrasting it with, and thinking about it from the viewpoint of, the basic concepts related to the topic. 8. Analysis State that what has changed since the article was written? How do its lessons, ideas and theories still apply? To what extent has its issues been resolved? 9. General Critique In this section one should state his/her opinions of how well the authors presented and discussed the research results including interpretations in the article. It should contain both positive and negative comments with due justification. Following issues may be addressed: - Does it build upon the appropriate foundation (i.e., upon appropriate prior research)? - Is the approach and execution is correct? - Confidence with respect to the article’s results, and why? - Does article throws upon exclusive new ideas? - What are the article’s shortcomings and limitations? - Are all important aspects and issues of its domain covered? - Examine and comment the logic given in the article 10a. Further Critiques of a Conceptual Article One should examine the logic of the arguments made by the authors. Article shall be tested upon logical consistency, coherence in arguments, substance of article and focus. 10b. Further Critiques of an Empirical Article In this section the strength of the empirical evidence supporting the author’s argument shall be examined. Article shall be test upon clarity, theoretical grounding, design of hypotheses and research investigation, correctness (in measurements, analysis and inferences drawn). 10c. Further criticises of a Review Article The logical sequence of background information and the focus as the state-of the art research should be examined. Article should be checked upon clarity, theoretical background, latest literature & critical review, scope for further research in the related area. 11. Issues (as listed by author) State issues as listed by author. How they are addressed or not addressed? 12. Issues (as per your opinion) State issues according to you which remain unresolved or issues which could arise in future. Also, provide suggestions for resolving them. 13. Relevance/Impact Determine how much this article has relevance/Impact, do a citation analysis. 14. Questions List three insightful questions of your own arising from this article that could really make one think. 15. Annotated Bibliography For every item you have cited in your review, you need a full reference and an annotation explaining it, as under: 1. List the full bibliographic references 2. Write 2-4 sentences describing the article. 3. Write 2-4 sentences describing why you cited it. REVIEW OF A JOURNAL ARTICLE: AN EXAMPLE o Bibliography Author, F. (1776). Effects of classroom testing by microcomputer. Journal of ABCDE, 99(9), 9-19. o Problem Microcomputers are being used for a variety of purposes, but research about their instructional effectiveness lags behind adoption rates for the technology. Further, there is a limited research base about the effects of microcomputers in vocational agriculture on learning in the affective, cognitive, and psychomotor domains. The research base is even more shallow when effects of testing students by computer technology are explored. Comments: The problem statements agreed with the title and seemed to be of educational significance. The problem was not clearly visible to the average reader, and it required several readings to establish why the researchers felt this study needed to be done. It was limited to the researchers’ capabilities and resources. o Review of Literature o The author cited no clear review of literature; however, several appropriate references were used in the introduction section. These statements contributed to the overall understanding of the subject and to the reasoning for establishing the problem statement. Suggested section titles would have been: (1) competencies vocational education teachers need to use computer technology effectively; (2) effects of microcomputers on learning; and (3) effects of testing students by microcomputer. o Hypothesis This research tested hypotheses about how effectively microcomputers could be used to administer an objective classroom test to students who had studied and used computer technology. Comments: The purpose was clearly and concisely stated and agreed with the title. It was limited to the researchers’ capabilities and resources. o Objectives Specifically, the study sought to determine: (a) the effect taking an objective final examination by microcomputer would have upon student cognitive performance; (b) the effect this method of testing would have on student attitude about computers immediately after the examination; and (c) whether this method of testing would require more time than conventional paper and pencil testing procedure. Comment: The author’s objectives were answerable, and they chose to obtain them by testing null hypotheses. These hypotheses were testable and served to help explain the problem. o Methodology The treatment followed the post-test only control group design; consequently, the study involved two replications. Both replications were conducted during a Nostate State University course. A two stage random assignment was used in assigning groups and treatments. The three dependent variables measured in this study were: (a) minutes to complete the test; (b) score on the test; and (c) score on the attitudes about computers. Comments: The methods used to gather the data for this article were clearly explained. The instruments and development were explained, and the reliability coefficients of all possible tests were given. The population used was adequate. No discussion of the statistical techniques was given in this particular section. o Findings Personal data by treatment and control group was provided in table form and explained with a short narrative. Hypothesis one: A one way analysis of covariance revealed that the two groups were not significantly different in terms of their scores on the 35 item final examination. Hypothesis two: The mean attitudinal scores of the two groups were positive in both replications, and there was no significant difference in the two groups’ attitudes about computers. Hypothesis three: There was a significant difference in minutes required to complete the exam in replication one; however, there was no significant difference in replication two. Comments: The findings were well organized, sectioned, and reported objectively. The tables were well organized but, due to the difficulty of the statistical tests employed, would not stand alone to the average reader. o Summary There was no summary given. o Conclusions Conclusions and implications were formulated with the knowledge that subjects for this study used microtechnology extensively during a computer applications course. In this investigation, final examination scores were independent of the method of testing. The method of testing was not a determinant of how students felt about computers. Since time required was not consistent over the two replications, the methods of testing as well as other factors appear to influence the time requirements of test completion. Comments: The conclusions were based on the findings and logically stated. o Recommendations "Additional research is needed in other classroom settings to see if consistent findings about cognitive performances, time requirements, and attitude are achieved." Comments: The recommendations were limited to a call for additional research in the area. o Overall Critique This was a very in-depth research project, particularly for a journal article. For the most part, it was well written and well organized. There was a definite need for a short review of literature to develop the situation. The article did get a little complicated in the reporting of data due to the complicated statistical procedures used. Overall, it was a very interesting, significant contribution to the field of research.