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WileyInterdiscipRevNanomedNanobiotechnol.Authormanuscript;availableinPMC2015
November01.
Publishedinfinaleditedformas:
WileyInterdiscipRevNanomedNanobiotechnol.2014November;6(6):532547.doi:10.1002/wnan.
1282.

Nanoparticle Approaches against Bacterial Infections

Weiwei Gao, Soracha Thamphiwatana, Pavimol Angsantikul, and Liangfang Zhang

Department of NanoEngineering and Moores Cancer Center, University of California, San Diego,
La Jolla, CA 92093, USA

Abstract

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Despitethewidesuccessofantibiotics,thetreatmentofbacterialinfectionstillfacessignificant
challenges,particularlytheemergenceofantibioticresistance.Asaresult,nanoparticledrug
deliveryplatformsincludingliposomes,polymericnanoparticles,dendrimers,andvarious
inorganicnanoparticleshavebeenincreasinglyexploitedtoenhancethetherapeutic
effectivenessofexistingantibiotics.Thisreviewfocusesonareaswherenanoparticleapproaches
holdsignificantpotentialtoadvancethetreatmentofbacterialinfection.Theseareasinclude
targetedantibioticdelivery,environmentallyresponsiveantibioticdelivery,combinatorial
antibioticdelivery,nanoparticleenabledantibacterialvaccination,andnanoparticlebased
bacterialdetection.Ineachareawehighlighttheinnovativeantimicrobialnanoparticleplatforms
andreviewtheirprogressmadeagainstbacterialinfections.

Keywords
Nanomedicine;nanoparticles;bacteria;infectiousdiseases;antimicrobialdelivery

1. Introduction
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Despitetheprofoundsuccessachievedbytheuseofantibioticsagainstinfectiousdiseases,
1,2

bacterialinfectionscontinuetoimposesignificantchallengesonglobalhealthcare .
Eradicationofcertainbacterialinfectionssuchastuberculosisremainsdifficultduetothe
complexmechanismsofthepathogeninsubvertingitshostsimmunesystemaswellasthe
3,4

deliverybarriersthatpreventantibioticsfromreachingsitesofinfection .Highlypotent
antibiotics,includingcertainaminoglycosidesandfluoroquinolones,generatesevereadverse
5,6

effectsandarereservedonlyforseriousinfections .Moresignificantly,theemergenceof
antibioticresistancehasgeneratedalarmingimpact,threateningtosetbacktheprogress
7,8

againstarangeofinfectiousdiseasestothepreantibioticera .Thewidespreaddrug
resistanceisfurtherexacerbatedbytheretreatofthepharmaceuticalsectorfromnew
9

antibioticdevelopment .Thesechallenges,together,highlightthedemandforalternative
andeffectiveantimicrobialstrategies.
Overthelastfewdecades,theapplicationofnanotechnology,particularlytheuseof
10,11

nanoparticlesfordrugdelivery,hasgeneratedsignificantimpactinmedicine
.Various
nanoparticledeliveryplatforms,especiallyliposomes,polymericnanoparticles,dendrimers,

Correspondingauthor:Tel:8582460999,zhang@ucsd.edu.

Gaoetal.

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andinorganicnanoparticles,havereceivedsignificantattention(Figure1).Drugmolecules
loadedintonanocarriersthroughphysicalencapsulation,adsorption,orchemical
conjugationexhibitanimprovedpharmacokineticprofileandtherapeuticindexwhen
12

comparedtotheirfreedrugcounterparts .Otheradvantagesofnanoparticledelivery
systems,includingimproveddrugsolubility,prolongedsystemiccirculation,sustainedand
controlledrelease,precisedrugtargeting,andconcurrentdeliveryofmultipledrugs,have
13

alsobeenvalidatedinvariousstudies .Asaresult,anumberofnanoparticlebaseddrug
deliverysystemshavebeenapprovedforclinicalusetotreatavarietyofinfectiousdiseases,
andmanyotherantimicrobialnanoparticleformulationsarecurrentlyundervariousstages
14

ofpreclinicalandclinicaltests .
Astheabilitytoengineermultifunctionalnanoparticlescontinuallyadvances,numerous
innovativeapproacheshaveemerged,furtherimprovingonnanoparticletherapeuticefficacy
againstbacterialinfection.Inthisreviewarticle,weselectfiveareaswherenanoparticle
approachesholdsignificantpotentialtoimproveuponcurrenttreatments.Theseareasinclude:
(1)targetedantibioticdelivery,(2)environmentallyresponsiveantibioticdelivery,

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(3)combinatorialantibioticdelivery,(4)nanoparticleenabledantibacterialvaccination,and
(5)nanoparticlebasedbacterialdetection.Progressesmadeintheseareasoffer
tremendousopportunitiesforalternativeandmoreeffectiveantimicrobialstrategiesthat
alterthepharmacokineticsofexistingantibiotics,producenewantibioticswithnovel
microbialinhibitionmechanisms,orallowformorerapidandsensitivemicrobial
detection.Collectively,theyaddresstheaforementionedchallengesincludingovercoming
antibioticresistance.Herein,werevieweachareawithhighlightsofthecurrentand
forthcomingnanoparticleplatformsagainstbacterialinfections.

2. Targeted antibiotic delivery

Bacterialinfectionincreasesvascularpermeability,whichmakespassivetargetingpossible.
Attheinfectionsites,thereleaseandaccumulationofbacterialcomponentssuchas
bacterialproteaseandlipopolysaccharidefromgramnegativebacteriaorlipoteichoicacid
fromgrampositivebacteriaareknowntotriggervariousinflammatorymediatorsthat
15,16

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directlystimulatevascularpermeability
.Thesebacterialcomponentsalsoactivate
immunecells,whichinturninteractwithvascularendotheliumthroughmultiple
inflammatoryandvascularmediators,leadingtogapwidening,barrierdysfunction,and
17

eventuallyincreasedpermeability .Moreover,dysfunctionallymphaticdrainagehasalso
beenreportedinbacterialinfection,whichpotentiallypromotesnanoparticleaccumulation
18

atthesitesofinfection .Thesefeaturesofbacterialinfectionsuggestthattheenhanced
permeationandretention(EPR)effectcanbeharnessedbynanoparticlesfortargeted
19

antibioticdelivery .Infact,bothuncoatedliposomesandPEGylatedliposomeshavebeen
showntoaccumulateselectivelyatsofttissueinfectedbyStaphylococcusaureus(S.
2023

aureus),andtheirretentiontimescorrelatedcloselywithsize
.Similarresultswere
observedforsuperparamagneticironoxidenanoparticles(SPIONs)atthesofttissueofrats
24

andinthelungsofmiceinfectedbyS.aureus .
Pathogenicbacteriamaintainanegativesurfacechargeunderphysiologicalconditions.
Therefore,cationicnanoparticlescapableofbindingwithbacteriaviaelectrostatic

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25,26

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interactionshavebeenexploredforeffectivebacterialtargeting
.Thisstrategyis
attractiveforitsmultivalenteffectandtheabilitytotargetpolymicrobialinfections.Asa
result,adiverserangeofbactericidalpolymersandpeptideshasbeenincorporatedinto
27

variousnanoparticledesignsforantibacterialapplications .Moreimportantly,
nanoparticleformulationcanincreasethelocalchargeandmassdensitiesofthebactericidal
components,resultinginenhancedtherapeuticindex.Forexample,aselfassembled
cationicpeptidenanoparticlehasshownstrongantimicrobialpropertieswhileinducing
28

minimalsystemictoxicity .Furthermore,improvingthebiodegradabilityofthe
nanoparticlescanfurtherreducecationicchargerelatedtoxicity.Inthisperspective,cationic
nanoparticlesselfassembledfrompolycarbonatebasedblockcopolymerswithhigh
biodegradabilityhavebeenshowntokillbacteriawithoutinducingobvioushemolytic
29

activityandsystemictoxicity .
Activetargetingwithpathogenbindingligandsdirectlyconjugatedtothesurfaceof
nanoparticlesisanotherstrategytotargetbacteria.Forexample,smallmoleculessuchas
30

vancomycinhavebeenconjugatedtothesurfacesofdendrimers ,ironoxide

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31

32

33

nanoparticles ,goldnanoparticles ,andporoussilicananoparticles ,resultingin

preferentialbindingofnanoparticlestogrampositivebacteria.Thetargetingefficiencyof
smallmoleculeswasalsofoundtobestronglydependentonmolecularorientation,surface
34

density,andlengthofthespacerusedinconjugation .Inadditiontosmallmolecules,
lectins,particularlythosewithselectiveagglutinationactivities,havealsobeenusedas
35

ligandstotargetbacteria .Polymericnanoparticlesconjugatedwithmannosespecificor
fucosespecificlectinsshowedenhancedbindingaffinitytothecarbohydratereceptorson
Helicobacterpylori(H.pylori)surfaces,suggestingapromisingapproachforsitespecific
36

andgastroretentivedrugdeliverytotreatH.pyloriinfection .Besideslectins,other
37

38

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proteinligandssuchassingledomainantibodies andbacteriophagetailspikeproteins
arehighlyspecifictargetingligandsandtheirconjugationtonanoparticleshasresultedin
targeteddeliveryplatformseffectiveagainstavarietyofbacterialinfections.Furthermore,
aptamershavealsobecomeaclassofattractivetargetingmoietiesowinglargelytothe
advancementinbacteriumbasedaptamerselectiontechniques,whichcontinuallyimprove
aptamerbindingaffinityandspecificity.Thesetargetingmoleculeshavebeenextensively
exploredtotargetnanoparticlestopathogenicbacteriasuchasSalmonellatyphimurium(S.
typhimurium)andMycobacteriumtuberculosis(M.tuberculosis)

39,40

Moreover,bacteriacansurviveingestionbyphagocyticcellssuchasmacrophages,hence
3

evadingtheimmunesystemandthebactericidalactionofantibiotics .Howevermacrophages
41,42

areabletotransportdrugstothesiteofinfectionbyachemotacticmechanism
.
Therefore,targetingantimicrobialnanoparticlestomacrophagesasopposedtobacteriahas
becomeanattractivestrategyforimprovingantibiotictherapy,particularlytotreat
43

intracellularbacterialinfection .Ithasbeenobservedthatfollowingpassivetargetingtothe
infectionsites,nanoparticlescouldpreferentiallybetakenupbymacrophagesduetothe
spontaneousscavengingfeatureofmacrophages

23,24

.Suchmacrophageuptakecouldbe

furtherenhancedbyattachingtargetingligandsontothenanoparticles
variousligands,includingmannose,maleylatedbovine

44,45

.Inthisregard,

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serumalbuminandOsteroylamylopectin,havebeenappliedtosuccessfully
enhancemacrophageuptakeofnanoparticlesforthetreatmentofintracellular

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infection

46,47

3. Environmentally responsive antibiotic delivery

Tofurtherimproveuponthetherapeuticefficacyofantimicrobialnanoparticles,
researchershaveexploredenvironmentallyresponsivenanoparticlesthatremaininactive
untiltheyaretriggeredbycuesfoundinthemicroenvironmentofinfectionsites.These
externalstimulicanbephysicalsignalssuchastemperature,electricfield,magneticfield,
andultrasound;theycanalsobechemicalsignalssuchaspH,ionicstrength,redox
48

potential,andenzymaticactivities .
Amongtheseenvironmentalstimuli,pHgradientshavebeenwidelyusedtodesignnovel,
responsivenanoparticlesforantibioticdelivery.Attheorganlevel,nanoparticleshavebeen
49

designedtorespondtothepHgradientalongthegastrointestinal(GI)tract andtheacidic
50

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environmentofhumanskin forsitespecificantibioticdelivery.Attheintracellularlevel,
nanoparticleshavebeenformulatedtorespondtotheacidicpHinsidetheendolysosomal
5153

compartmentsfortriggereddrugrelease
.InadditiontopHgradient,bacterialenzymatic
activities,includingthoseofsecretedtoxins,havealsobeenusedtotriggerthereleaseof
antimicrobialagentstoinhibitthegrowthofthetargetbacteria.

Chargedpolymershavebeenadsorbedontoliposomesurfaceswithoppositechargeto
54,55

stabilizetheliposomes
.SuchstabilizationispHsensitiveandhasbeenextensively
usedtotreatvariousintracellularbacterialinfectionsincludingSalmonellaenterica(S.
56,57

58,59

enterica)
aswellascasesofsepticshock
.Basedonasimilarmechanism,ionic
liposomescanbeemployedtocarryoppositelychargeddrugmoleculesforpHsensitive
drugrelease.Inaddition,loadingliposomeswithmembranedisruptingtoxinssuchas
60

hemolysin andlisteriolysinthatareresponsivetoendosomalacidificationhasalso
61

shownpotentialforthetreatmentofintracellularinfections .

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Recently,anewenvironmentresponsivedeliverystrategyhasemergedthatinvolvesthe
attachmentofsmallchargednanoparticlesontoliposomesurfacesforliposomestabilizationand
triggeredantimicrobialdelivery(Figure2).Thenonspecificadsorptionofchargednanoparticles
ontophospholipidbilayersprovidedstericrepulsionthatinhibitedliposomefusion.Italso
reducedliposomesurfacetensionandthusfurtherenhancedliposomestability

62,63

Intriguingly,thechargeandchargedensityofboththenanoparticlestabilizersandtheliposomes
couldbepreciselytailoredtoenablestimulusresponsivebindinganddetachmentofthe
nanoparticles,therebyallowingforanondemandcontroloverliposomefusionactivityfor
smartdrugdelivery.Forinstance,cationicliposomesboundwithnegativelychargedgold
nanoparticlesonlyfusedwithbacteriaatacidicpH,whichmadethemsuitablefortreating
variousskinpathogensthatthriveinacidicinfectionsitessuchasthecasewith
64

Propionibacteriumacnes(P.acnes) .Conversely,anionicliposomesstabilizedbypositively
chargedgoldnanoparticleswerehighlystableingastricacid,butcapableoffusingwithbacteria
65

atphysiologicalpH,makingthemsuitabletotreatgastricpathogenssuchasH.pylori .Even
intheabsenceofsuchstimulusinduceddetachmentofthenanoparticlestabilizers,these
liposomesstillhadasubstantialfractionof

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theirsurfaceareasexposedandhighlyaccessibletobacterialtoxins.Thisfeature
allowedtheliposomestorespondtovariousbacteriasuchasS.aureusthatsecretpore

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66

formingtoxinstotriggerdrugreleasefromtheliposomes .Aimedatimprovingthe
topicalapplicationsofnanoparticlestabilizedliposomes,ahydrogelformofthedelivery
systemwasrecentlydeveloped,whichnotonlypreservedthestructuralintegrityofthe
nanoparticlestabilizedliposomes,butalsoallowedforcontrollableviscoelasticityand
67

tunableliposomereleaserate .
Meanwhile,polymericnanoparticleshavebeenextensivelystudiedforresponsiveantibiotic
delivery.Forexample,triblockcopolymernanoparticlescomposedofpoly(lacticco
glycolicacid)(PLGA),poly(Lhistidine)andpoly(ethyleneglycol)(PEG)havebeen
68

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reportedforacidresponsiveantibioticdelivery .Thesenanoparticlesmaintaineda
negativechargeatneutralpH;however,whenexposedtoanacidicpH,theprotonationof
theimidazolegroupsswitchedthesurfacechargetoapositiveone,resultinginenhanced
bacterialbindingandimprovedantibacterialefficacy.Asanotherexample,heparinand
chitosanhavebeenappliedtoformbasesensitivenanoparticlesfortreatinggastric
pathogenssuchasH.pylori.ThepolymersselfassembledtoformnanoparticlesatpH1.2
2.5;however,uponcontactwithH.pyloriatthegastricepitheliumwithphysiologicalpH,
thechitosandeprotonated,causingnanoparticledisassemblyandreleaseofdrugsfor
69

bacteriakilling .Moreover,bytailoringthepKaofamphiphiliccopolymers,awiderange
ofpolymericnanoparticleshasbeenengineered,whichpreciselyrespondtothesubtle
changesofpHalongtheGItractforsitespecificantibioticdelivery.Enzymesensitive
polymericnanoparticleshavealsobeendevelopedforintracellulardeliveryinmacrophages.
Forexample,atriplelayerednanogelformulationhasbeenreported,whichcontaineda
bacteriallipasesensitivepoly(caprolactone)interlayerbetweenthecrosslinked
70

polyphosphoestercoreandthePEGshell .Followingmacrophageuptake,thepresenceof
bacterialphosphataseorphospholipasetriggeredrapiddrugrelease,whichsubsequently
47

inhibitedthegrowthofS.aureus .

4. Combinatorial antibiotic delivery

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Combiningtwoormoredistinctantibioticsrepresentsacommonstrategyintreating
bacterialinfectionswiththeaimtobroadentheantimicrobialspectrum,generatesynergistic
effects,andcounteractantibioticresistance.However,varyingpharmacokinetics,
biodistributions,toxicityprofiles,andmembranetransportpropertiesamongdifferentdrug
compoundscomplicatedosingandschedulingoptimization,whichinturncompromisedrug
71

synergyinvivo .Inthisregard,nanoparticlesofferuniquepropertiestoenhance
combinatorialantibioticdeliveryandnumerousapplicationshavebeeninvestigatedto
addressavarietyofbacterialinfections(Table1).
Liposomesareahighlyversatileplatformforcombinatorialdelivery.Hydrophilicdrugscan
bedirectlyencapsulatedintheaqueouscompartmentsofliposomes,whilehydrophobic
72

drugscanbeincorporatedintothelipidbilayermembranes .Forexample,isoniazidand
rifampicin,firstlineantituberculardrugs,havebeenloadedintheaqueouscompartment
andthelipidbilayer,respectively.Theresultingliposomalformulationhasshownincreased
efficacycomparedtofreedrugcounterpartsatthesamedosages

7375

.Liposomal

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formulationcanalsoreducedrugtoxicitytothehostcells,therebyallowingforcodelivery
ofcombinatorialantibioticsthatareotherwisetootoxicintheirfreeforms.Forexample,
drugcompoundssuchasgallium(Ga)andbismuthderivativesareantibioticsthatinhibit
bacterialgrowthbyinterruptingtheirironuptake.Althoughtheyhaveshownsynergetic
effectsincombinationwithotherantibiotics,theirusagehasbeenlimitedbysevere
76

3+

toxicity .Toaddressthischallenge,Ga wascombinedwithgentamicinandloadedinto

liposomes.TheformulationreducedGatoxicityandimprovedefficacyagainsthighly
77

resistantPseudomonasaeruginosa(P.aeruginosa) .Similarly,bismuthethanedithiol
(BiEDT)wasencapsulatedtogetherwithtobramycinintoliposomes,resultinginthe
eliminationofBiEDTstoxiceffectonhumanlungcellswhileincreasingitsantibacterial
7880

efficacyagainstP.aeruginosaandBurkholderiacepacia(B.cepacia)
.Arecentin
vivostudyshowedthatthesamedrugcombinationinaliposomeformulationenhanced
81

efficacyinreducingbacterialburdeninratschronicallyinfectedwithP.aeruginosa .

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Moreover,liposomalformulationofcombinatorialantibioticsenablesratiometriccontrol
overthedrugsandthusunifiesthepharmacokineticsofdifferentdrugmoleculesandensures
paralleltissuedistribution.Theseadvantagesservetoenhancetheantimicrobialefficacyof
thedrugs.Forexample,usingthedosageanddosingschedulederivedfrominvitrostudies,
thecoadministrationofgentamicinandceftazidimeonlyresultedinanadditiveeffectina
82

ratmodelofanacuteunilateralKlebsiellapneumoniae(K.pneumoniae)infection .In
contrast,thecorrespondingliposomalformulationencapsulatingbothgentamicinand
ceftazidimeshowedasynergisticeffectthatledtoashortercourseoftreatmentatlower
83

cumulativedoses .Thebenefitofratiometricdeliveryusingliposomeswasalsoreported
84,85

inothercombinationtherapiesintreatingS.aureus
Mycobacteriumavium(M.avium)

86,87

,andH.pylori

,M.tuberculosis

73,74

88,89

Polymericnanoparticlesrepresentanotheremergingplatformforcombinatorialantibiotic
deliverytotreatbacterialinfection.Ingeneral,drugmoleculescanbedirectlyencapsulatedinto
thepolymericcores.Forpreciseratiometricloadingandcontrolleddrugrelease,multipledrugs
canbecovalentlyconjugatedtothepolymerbackbonefollowedbynanoparticlepreparation

90

92

.Inaddition,usingemulsiontechniques,bothhydrophobicandhydrophilicdrugmolecules

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93,94

canbecoencapsulatedintothepolymericcores
.Asaresult,severalpolymeric
nanoparticlesystemshavebeenreportedfordeliveringantibioticcombinations.Forexample,the
combinationofrifampinandazithromycinwasdeliveredwithPLGAnanoparticlesandshowed
95

betterefficacyinvitrocomparedtofreedrugsintreatingpersistentchlamydialinfection .
Nanoparticlesmadeofgliadin,avegetalproteincommonlyderivedasafractionofwheatgluten,
wereusedtocoencapsulateclarithromycinandomeprazole,whichachievedbetterefficacy
againstH.pyloribacteriainrats

96,97

.Thegliadinnanoparticleswerefurtherconjugatedwith
98

lectinandusedintripletherapywithamoxicillin,clarithromycin,andomeprazole ,resultingin
superiorinvivoclearanceofH.pyloricomparedtothenonconjugatedformulationandfree
drugs.Moreover,PLGAnanoparticleswerealsousedfororaldeliveryofantituberculosisdrugs
99,100

(ATDs)
.In8)thesestudies,threeorfourfrontlineATDs,includingrifampicin,isoniazid,
pyrazinamideandethambutol,werecoencapsulatedinsidePLGAnanoparticlesthroughan
emulsion

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technique,andtheresultingnanoparticleformulationimprovedbacterialclearancein
M.tuberculosisinfectedmiceandguineapigsviaoraladministration.

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5. Nanoparticle-enabled antibacterial vaccination

Vaccinescanprotectagainstortreatinfectionsbymanipulatingthehostsimmune
responses,andtheirsuccessincontrollingformerepidemicsworldwidehasbeen
101,102

consideredasthemosteffectivepublichealthinterventioneverachieved
.The
vaccinestrategyalsoholdsthepromisetohaltantibioticresistancebyreducingthe
103,104

exposureofbacteriatowidelyusedantimicrobialagents
.However,themajorityof
existingvaccinespredominantlydrivethegenerationofneutralizingoropsonizing
antibodiesagainstpathogens,amechanismthatisineffectiveagainstanumberof
105

infections .Vaccinedevelopmentagainstthesediseasesisfurtherhamperedby
incompleteunderstandingoftheenormouslycomplexhumanimmunesystemandthe
underlyingmechanismsofprotection

106

.Toaddressthesechallenges,nanoparticlesoffer

uniqueadvantagesforimmunemodulationagainstbacterialinfections

107,108

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Nanoparticleshavebeenextensivelyexploredtoovercometheinstability,undesirable
systemicbiodistribution,andtoxicityfrequentlyassociatedwiththeadministrationofsoluble
molecules

109,110

.Ithasbeenreportedthatconjugationofantigenstonanoparticlesurfaces

facilitatedBcellactivation

111

,duetoahigherquantityofantigensthatweredeliveredto
112

antigenpresentingcells(APCs) .Withtheadvancementinnanoparticleengineering,
fabricationtechniqueslongestablishedformanufacturingnanoparticlebaseddrugdelivery
systemsincludinglayerbylayerassembly

113,114

,facilespraydryingprocess

115

,andsoft

116

lithographybasedPRINTtechnology havealsobeenincreasinglyappliedtoimproveon
antigenloading.Recently,naturalcellularmembranecoatednanoparticleshavealsobeen
showntodetainmembranedamagingtoxinsanddivertthemawayfromtheircellular
117,118

targets
.Suchatoxindetainmentstrategywasappliedtosafelydeliverintact
staphylococcalhemolysintoAPCsandinducedsuperiorprotectiveimmunityagainsttoxin
mediatedadverseeffectsinmicewhencomparedtovaccinationwithheatdenaturedtoxins
119

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(Figure3) .Thisapproachmaintainedafaithfulantigenicpresentationwhileremoving
toxinvirulence,thereforeavoidingthetradeoffbetweenefficacyandsafetythatremainsa
majorchallengeofcurrenttoxoiddevelopment.
Besidesdeliveringantigens,nanoparticlescanconcurrentlycarryadjuvantstomimicnatural
120,121

microbesforenhancedvaccinationefficacy
.Particularly,varioustolllikereceptor(TLR)
ligandsincludingsmallmolecules,carbohydrates,DNAs,andRNAs,togetherwithantigenshave
beendeliveredusingnanoparticles,resultinginequivalentimmuneresponsescomparedto
122125

solubleantigenformulationsbutatsignificantlyreduceddosages
.Moreimportantly,
nanoparticlesallowforprogrammablepresentationofadjuvantsandantigenstoimmunecellsfor
desirableresponses.Forexample,combinationsofTLRagonists,asopposedtoasingleadjuvant,
havebeenconcurrentlyloadedintonanoparticlestomimicthecombinatorialTLRactivationthat
126128

occursinnaturalinfections,thereforeresultinginmorevigorousimmuneresponses
.In
addition,nanoparticlesallowforthesequentialpresentationofantigensandadjuvantstobe
programmedforoptimalimmuneresponses.Forexample,encapsulationofantigensandTLR
agonistsintothesamenanoparticleshasshown

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advantagesfortheinductionofeffectorTcellresponses

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antigenprocessingoccursindendriticcells

130,131

124,129

duetothemannerinwhich

.Incontrast,deliveryofantigensandTLR
132

agonistsinseparatenanoparticlesseemedtobenefitantibodyresponses .Recentadvancement
incontrollingtheintrananoparticlearchitectureandadjuvantdistributionhasprovided
133

additionalcapabilityforprogrammingnanoparticlebasedimmunemodulation .Forexample,
whenaninterbilayercrosslinkedmultilamellarvesicleswereusedassyntheticvaccines,the
TLR4agonistmonophosphoryllipidA(MPLA)wasincorporatedthroughoutthevesiclelayers
andelicitedstrongerserumIgGtitresascomparedtothevesiclescarryingthesameamountof
MPLAbutattachedonlyonthevesiclesurfaces(Figure4)

134

Targetingvaccinestodesiredsitesforsafeandeffectiveimmuneresponsesisanother
advantageofusingnanoparticlesforvaccinedelivery.Forexample,acationicnanogel
loadedwithasubunitfragmentofClostridiumbotulinum(C.botulinum)typeAneurotoxin
hasbeenshowntofacilitatepersistentantigenadherencetothenasalepitheliumand
135

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effectiveuptakebymucosaldendriticcells .Thisplatformnotonlyelicitedstrong
systemicandmucosalimmuneresponses,butalsopreventedexposureoftheupper
respiratorytractandthecentralnervoussystemtotoxicantigens.Asanotherexample,
nanoparticlesresponsivetothepHgradientoftheGItracthavebeenabletoprotectantigens
whileinthestomachbutreleasetheminthelowerGItractforsubsequenttranslocation
acrosstheintestinalepithelium

136

.Asimilarstrategyhasalsoshownpromisefortargeting
137

antigentranscytosingMcellsoverlyingPeyerspatchesforfurtherenhancedimmunity .
Inaddition,nanoparticlebasedvaccineplatformscaneffectivelytargetlymphnoderesiding
immunecells.Ithasbeenshownthatsmallernanoparticlestransportfastertothelymph
138

139

node ,butlargerparticlesareretainedlongerwithinthelymphnode .Suchdistinct

correlationsindicatetheimportanceofsizeoptimizationinlymphatictargetingfordesired
immuneresponses.Atthesinglecelllevel,numerousnanoparticleformulationshavebeen
140142

designedtoescapeendosomesfollowingtheiruptakebyAPCs
.Thesenanoparticles
specificallydepositedvaccinepayloadsintothecytosolandshowedpromisetoenhance
CD8+Tcellpriming.

6. Nanoparticle-based bacterial detection

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Rapidandsensitivebacterialdetectioniscrucialforidentificationoftheinfectionsource,
allowingfortreatmentwiththeappropriateantibioticsandthuspreventingthespreadofthe
143,144

disease
.Bacterialcultureandbiochemicalstainingremainthecurrentgoldstandard
intheclinicdespitelaboriousprocessing,longproceduraltimesandlimitationsin
identifyingcertainpathogenicspecies.Amongthevariousexistingdiagnosticapproaches,
thosebasedonpolymerasechainreaction(PCR)andsequencinghaveshownparticular
145,146

promiseashighlysensitivetoolsformicrobialidentification
.However,quantitative
realtimePCRbasedsystemsareoftentooexpensiveinresourcelimitedsettings,andthe
147,148

currentsequencingtechniquesstilllackpracticalapplicabilityforpatientcare
.In
thisregard,nanoparticlesofferuniqueopportunitiesforgeneric,accurateandpointofcare
detectionofpathogens

149,150

Usingconventionalorganicfluorophoresforbacterialdetectionislimitedbythe
moleculesshortlifetimeandlowsensitivity.Toovercomethesechallenges,silica
nanoparticleshave

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beenusedtoencapsulatethousandsoffluorescentmoleculesinasingleparticle,resultingin
151

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significantlystrongerfluorescencesignals .Thisstrategyhasresultedinultrasensitive
bacterialdetectionatasinglecelllevel.Meanwhile,semiconductorquantumdots(QDs)have
alsoemergedasapromisingclassoffluorophoresforbacterialdetection.Comparedtoorganic
fluorephores,QDsarebrighterandmorestable;theyalsoexhibitbroadabsorptionandnarrow
152

emissionspectra,apropertyusefulforsimultaneousexcitationanddetection .Ligand
conjugatedQDshavebeenextensivelyexploredforthedetectionofvariousbacteria,including
Escherichiacoli(E.coli),S.typhimurium,Mycobacteriumbovis(M.bovis),andoral
153155

bacteria
.Additionalstrategieshavebeenexploredtofurtherimprovethesensitivityof
QDbasedbacterialdetectionsystems.Forexample,thebindingaffinityofQDscoatedwith
zinc(II)dipicolylaminecoordinationcomplexes,abacterialligand,hasbeenshowntocorrelate
156

tothesizeoftheQDs .Basedonthisobservation,QDswithtailoredsizeshavebeen
developedtodistinguishdifferentmutantsofthesamebacterialspecies.Asanotherexample,
streptavidincoatedQDshavebeenusedtolabelengineeredbacteriophagesfollowinganinvivo
157

amplificationandbiotinylationprocess .Thismethodenabledspecificdetectionofasfewas
10bacteriapermilliliterintestingsamples.

NIH-PA Author Manuscript

Besidesfluorescencebaseddetectiontechniques,ironoxidenanoparticleshavereceived
158,159

muchattention,owinglargelytotheirintrinsicmagneticproperties
.Ironoxide
nanoparticlescoatedwithpathogenspecificantibodieshavebeenwidelyusedtoisolate
160,161

livingbacteriafromhumanbloodsamplesunderamagneticfield
.Morerecently,
thistechniquehasbeencoupledwithmicrofluidictechnologyandhasresultedinhigh
162164

throughputbacterialdetectionundervariousclinicalsettings
.Meanwhile,
paramagneticironoxidenanoparticlesthatallowforsignalreadoutwithmagnetic
resonanceimaging(MRI)systemshavebecomeanattractivenewoptionforultrasensitive
bacterialdetection.Forinvitrodiagnosis,ironoxidenanoparticleswithadiameterof21nm
havebeencoupledwithaDNAhybridizationtechniquetoenhancethecapturingof
bacterial16SrRNAswithaminiaturizedmicroNMRsystem,resultinginrapidandspecific
165

pathogenprofilinginclinicalsamples(Figure5) .Forinvivodiagnosis,ironoxide
nanoparticleshavealsobeenexploredtodetectavarietyofpathogenicbacteriainanimal
models,wherethehighspatialresolutionandexcellentsofttissuecontrastofMRIprovided

NIH-PA Author Manuscript

informationonbothbacteriallocalizationandcorrespondinghostresponses

166

Goldnanoparticlesareanotheremergingnanoparticleplatformforbacterialdetection.These
nanoparticlespossessstronglightscatteringpropertiesandchangetheirplasmonresonance
spectrumuponaggregation.Thisphenomenonhasbeenwidelyexploredforthedetectionof
167

bacteriaspecificDNAs,proteins,andlivebacteria .Forexample,individualgold
nanoparticleshavebeenpreciselycrosslinkedwithswitchablelinkers,whichweredesignedto
168

breakinthepresenceoftargetsubjects .Asaresult,thisdesignamplifiedthepathogen
inducednanoparticleaggregationdispersionprocessandallowedforvisibledetectionofE.coli
ataconcentrationof100CFU/mL.Inaddition,goldnanoparticlescannonspecificallyquench
fluorescentmolecules.Basedonthisphenomenon,afluorophoredisplacementstrategyhasbeen
169

developedforbacterialdetection .Inthisstrategy,goldnanoparticlesadsorbedwith
fluorescentpolymerssuchaspoly(paraphenyleneethynylene)andpolylysineselectively
interactedwithbacteriaandreleasedtheboundfluorescentpolymerswhichwere

WileyInterdiscipRevNanomedNanobiotechnol.Authormanuscript;availableinPMC2015November01.
Gaoetal.

Page10

initiallyquenchedbythegoldnanoparticles.Therecoveredpolymerfluorescenceallowed
fortheeffectiveidentificationofbacteriawithinminutes.

NIH-PA Author Manuscript

Recently,rapidprogresshasbeenmadebyintegratingnanoparticlebasedmicrobial
detectionintominiaturizeddevicessuchasmicrofluidicsystemsandlabonachipfor
broaderapplications

170

.Thesedevicespotentiallyperformassayswithadequate
163,171

sensitivity,specificityandreproducibility,yetdemandlittleuserinput
.The
combinationofnanoparticlebaseddetectionprincipleswithsuchdevicesprovide
unprecedentedopportunitiesinunderdevelopedregionstoperformroutinetests,detectthe
presenceofaninfectiousagentwithepidemicpotential,andprovideguidanceforthe
regionaldiseasecontrol.

7. Conclusions

NIH-PA Author Manuscript

Theadventofnanotechnology,particularlynanoparticleengineering,togetherwiththe
accumulationofknowledgeoninfectiousdiseases,hasallowedforsignificantadvancement
inthefieldofantibacterialdrugdelivery.Majoreffortshavebeendevotedtodeveloping
variousnanoparticlebaseddeliveryplatformsincludingliposomes,polymericnanoparticles,
dendrimers,andinorganicnanoparticles.Thesenanoparticleapproacheshaveshown
excellentoutcomesintreatinganddetectingbacterialpathogensbyenablingtargeted,
responsive,andcombinatorialdeliveryofantibiotics,effectiveantibacterialvaccination,and
rapiddetectionofbacteria.Itisexpectedthatnanotechnologywillcontinuebringing
improvementstoantimicrobialdeliverysystemsforefficacious,patientcompliant,andcost
effectivetherapeuticsaswellasthespecificandsensitivedetectionofvariousinfectious
diseases.

Acknowledgments
ThisworkissupportedbytheNationalInstituteofDiabetesandDigestiveandKidneyDiseasesofthe
NationalInstitutesofHealthunderAwardNumberR01DK095168.

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Figure1.

Schematicillustrationofmajornanoparticlebaseddeliveryplatformsfortreating
bacterialinfections:(A)liposome,(B)polymericnanoparticle,(C)dendrimer,and(D)
inorganicnanoparticle.

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Gaoetal.

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Figure2.

Schematicillustrationofaphospholipidliposomestabilizedbychargedgoldnanoparticles
anditsdrugreleaseinresponsetopHchangeorthepresenceofbacterialtoxin.

NIH-PA Author Manuscript

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Figure3.

Schematicpreparationofnanoparticledetainedtoxins,denotednanotoxoid,consistingof
substratesupportedRBCmembranesintowhichporeformingtoxinscanspontaneously
incorporate.Reproducedwithpermissionfromreference119.

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Gaoetal.

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Figure4.

Schematicillustrationofinterbilayercrosslinkedmultilamellarvesicles(ICMVs)for
vaccinedelivery:(A)OVAloadedICMVswithMPLAonlyontheexternalsurface,and
(B)OVAloadedICMVswithMPLAthroughoutthelipidmultilayers.Reproducedwith
permissionfromreference134.

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Figure5.

MagnetoDNAassayforthedetectionofbacterial16SrRNA.TotalRNAisextractedfrom
thespecimen,andthe16SrRNAisamplifiedbyasymmetricRTPCR.SinglestrandDNA
oftheamplifiedproductisthencapturedbybeadsconjugatedwithcaptureprobes,followed
byhybridizingwithMNPstoformamagneticsandwichcomplex.Samplesaresubsequently
analyzedusingaminiaturizedmicroNMR(NMR)system.Reproducedwithpermission
fromreference165.

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Table 1

NIH-PA Author Manuscript

Combinatorialnanoparticlesforantibacterialdrugdelivery
Platform

NIH-PA Author Manuscript

Formulation

DrugCombination

Targetedbacteria

References

DPPC,DMPGand
cholesterol

Galliumandgentamicin

P.aeruginosa

[77]

DSPCandcholesterol

Bismuthethanedithiol(BiEDT)and
tobramycin

P.aeruginosaandB.
cenocepacia

[78]

PEGylatedliposome

Daptomycinandclarithromycin

MRSA

[85]

PG,PCandcholesterol

Clarithromycinandofloxacin

M.avium

[86]

PC,SA,andcholesterol

Ciprofloxacinandvancomycin

MRSA

[84

PC,PEGDSPE,and
cholesterol

Gentamicinandceftazidime

K.pneumoniae

[83]

DPPCandcholesterol

Isoniazidandrifampicin

M.turberculosis

[75]

PG,PCandcholesterol

Streptomycinandandciprofloxacin

M.avium

[87]

PC,PE,SAandcholesterol

Amoxicillintrihydrateandranitidine
bismuthcitrate

H.pylori

[88]

PAA,PAH,PC,and
cholesterol

Amoxicillinandmetronidazole

H.pylori

[89]

PLGA

Rifampinandazithromycin

C.trachomatisandC.
pneumoniae

[95]

PLGA

Rifampicin,isoniazid,pyrazinamide,
andethambutol.

M.tuberculosis

[99]

Sodiumalginateandchitosan

Rifampicin,isoniazid,pyrazinamide,
andethambutol.

M.tuberculosis

[100]

Chitosanandglutamicacid

Amoxicillin,clarithromycin,and
omeprazole

H.pylori

[97]

GliadinandPluronicF68

Clarithromycinandomeprazole

H.pylori

[98]

Gliadin,lectinandPluronic
F68

Amoxicillin,clarithromycinand
omeprazole

H.pylori

[96]

Liposomes

Polymericnanoparticles

Acronyms:
DPPC:1,2dipalmitoylsnglycero3phosphocholine,
DMPG:1,2dimyristoylsnglycero3phosphoglycerol
DSPC:1,2distearoylsnglycero3phosphocholine

NIH-PA Author Manuscript

DSPE1,2distearoylsnglycero3phosphoethanolamine
DPPC:dipalmitoylphosphatidylcholine
PG:eggyolkphosphatidylglycerol
PE:phosphatidylethanolamine
PC:phosphatidylcholine
SA:stearylamine
PLGA:poly(lacticacidcoglycolicacid)
PAA:poly(acrylicacid)
PAH:poly(allylaminehydrochloride)

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