review article immunomodulation of nanoparticles...

Review ArticleImmunomodulation of Nanoparticles inNanomedicine Applications

Qing Jiao1 Liwen Li1 Qingxin Mu23 and Qiu Zhang1

1 School of Chemistry and Chemical Engineering Shandong University Jinan 250100 China2 Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA3Department of Materials Science amp Engineering University of Washington Seattle WA 98125 USA

Correspondence should be addressed to Qingxin Mu qmuuwashingtonedu and Qiu Zhang zhangqiusdueducn

Received 2 November 2013 Accepted 7 January 2014 Published 20 May 2014

Academic Editor Sung Jean Park

Copyright copy 2014 Qing Jiao et alThis is an open access article distributed under the Creative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Nanoparticles (NPs) have promising applications in medicine Immune system is an important protective system to defendorganisms from non-self matters NPs interact with the immune system and modulate its function leading to immunosuppressionor immunostimulationThese modulating effects may bring benefits or danger Compositions sizes and surface chemistry and soforth affect these immunomodulations Here we give an overview of the relationship between the physicochemical properties ofNPs which are candidates to be applied in medicine and their immunomodulation properties

1 Introduction

Large surface area high aspect ratio small size and uniquephysical and chemical properties in NPs enable their poten-tial applications in many biomedicine fields such as drugand gene delivery imaging photodynamic therapy andtissue engineering [1ndash3] The small size of nanoparticls offersthem the ability to overcome various biological barriers totransport and deliver therapeutic agents to the target tissueNPsmay overcome drug resistance when functionalized withtargeting moiety [4ndash6] The ldquonanophotosensitizersrdquo used inphotodynamic therapy (PDT) show higher solubility thannormal photosensitizer playing an important role in thetreatment of cancer [2] Additionally the increased reso-lution and sensitivity give nanostructure-based diagnosticsan advantage over classical methods [7 8] Compared totraditional molecular medicine NPs show advantages suchas intermixing diffusion sensoric response and ultrafastkinetics make nanomedicine a local process at the nanoscale[9] At the same time NPs will enter and interact with humanbody during these processes

As an important protective system to defend organismsfrom foreign matters and danger signals inside the body theimmune system plays a critical role in keeping homeostasis

in human body The immune system exerts its functionthrough innate immunity and adaptive immunity Innateimmunity is the first line of defense against microbial inva-sion which interacts with the foreign materials and cleansthe pathogen or pathogen-infected cells which is nonspecificto pathogen The function of innate immunity was realizedby the phagocytic cells (macrophages dendritic cells (DCs)neutrophils and mast cells (MCs) etc) which phagocytosepathogen and release cytokine to clear pathogen If thepathogen cannot be effectively cleared by innate immunitythe adaptive immunity as the second line of defense inhuman body will be activated During these processessome phagocytic cells act as antigen-presenting cells (APCs)and present specific antigens to specialized cells which areresponsible for adaptive immunity such as T cells and Bcells By this antigen-presenting process pathogen (antigen)could be recognized by T cells and B cells and stimulatethe adaptive immune response which is specific to pathogen[10 11] The strong ability to eliminate pathogens makesthe immune system important in most disease treatmentHowever abnormal intensity of immune response includingimmunosuppression and immunostimulation will lead todisease [10] Immunosuppression can be caused by impair-ment of any component of the immune system which

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 426028 19 pageshttpdxdoiorg1011552014426028

2 BioMed Research International

results in a decreased immune function and thereby leads topathogen which cannot be effectively cleared and infection ortumorwill occur [12] Immunostimulation could enhance theability to resist pathogen but it may result in a strong adverseresponse such as autoimmune disease if it was hypersensitive

When nanomedicines are applied in vivo they act asforeignmaterials and induce the immune response immuno-suppression or immunostimulation [13] However thesemodulations of immune system caused by NPs are unde-sirable in most cases when nanomedicine is applied suchas imaging Furthermore these immune modulations byNPs could be adverse in other conditions Some nanobasedanticancer therapeutic agents show antitumor properties invitro but tumor-promoting effect in vivo [14] This oppositeeffect may be due to the disturbed anticancer immunesystem [14] However some immunomodulation propertiesare good for disease prevention and treatment such asvaccine adjuvant and antiallergy therapeutic agents [15 16]Therefore NPs play as a Janusrsquo double-face in nanomedicineapplications (Figure 1) Immunomodulating potential of NPsshould be considered seriously because it could bring unex-pected side effects in the clinical treatment Understandingof nano-immuno-interactions is critical for the safe appli-cation of engineered NPs in medicine and safe design ofnanomedicine

In this review we focus on the immunomodulatingeffects of NPs used in nanomedicine on immune system(Table 1) Effects of physicochemical properties of NPs onimmune interactions and the underlying mechanisms arealso reviewed

2 NPs Candidates Used in Nanomedicine

Nanotechnology has a great potential in medicine applica-tions such as medical diagnostics [60] and therapy [61] Asan inorganic fluorophore quantum dots (QDs) have pho-tostability which makes them ideal candidates for imagingtools in vivo [62] Recent study showed a technique to tracklymph flow in real time using quantum dots optical imagingin mice [22] In addition superparamagnetic iron oxideNPs (SPION) were also applied to trace neurodegenerativediseases by magnetic resonance imaging (MRI) [63] Somecarbon-based NPs are also applied in clinical use Carbonnanotubes (CNTs) have unique physical properties such aselectrical thermal and spectroscopic properties whichmakethem an advantage in detection and therapy of diseases [64]It was reported that CNTs could prolong survival of tumor-bearing animals [65] Graphene has good biocompatibilitybiofunctionalization and its unique mechanical electronicand optical properties for imaging and cancer phototherapy[66] And it was demonstrated that graphene oxide (GO)have antibacterial properties [67] making them candidatesas antibacterial agent Besides graphene derivatives are alsogood candidates for drug delivery as they can bind witharomatic drugs through120587-120587 stack andor van derWaals inter-actions [66] Gold NPs (GNPs) are also potential materials incancer therapies and imaging due to their biocompatibilityplasmon resonances and diverse functionalizations [68] It

Anti-inflammatory

Antiallergic

Vaccine adjuvantAnticancer

Antibacterial

Incapacitate bodyrsquos immunesystem to unwanted mass

Inflammation

Immunosuppression

Immunostimulation

Nanoparticles

Figure 1 The immunomodulation of NPs presents a Janusrsquo double-face in nanomedicine applications On one hand the effects to theimmune systemmay benefit treatment of disease through enhancingimmune response On the other hand the immunomodulation ofNPs may bring harm

is promising to apply GNPs to targeted therapy of cancer[69] and overcome drug resistance [6] Silver NPs (AgNPs)are important metal nanomaterial They have antibacterialantifungal and antiviral effects [70] Lipid NPs and liposomehave been widely applied for drug delivery because of theirimproved drug potency and low off-target effects [71] OtherNPs such as polymer CeO

2 silica NPs dendrimer and

protein NPs are also used in nanomedicine [72ndash78]As foreign materials NPs could be recognized by the

immune system and induce immunosuppression or immun-ostimulation when used as nanomedicine How to utilizeor control these immunomodulation effects is largely basedon NPsrsquo different applications NPs with immunosuppressioneffects might be used as anti-inflammatory or antiautoim-mune disease therapeutic agents On the contrast NPs whichactivate immune systemmight be used as vaccines or vaccineadjuvants An advanced nanomedicine in drug delivery orimaging should not induce undesired immune-activation orimmunosuppression effectThe detailed immunomodulationeffects of these NPs in nanomedicine applications are dis-cussed below

3 Immunomodulation by Different NPs

31 Immunosuppression

311 Carbon Nanotubes After inhalation exposure CNTsinduced systemic immunosuppression in mice includingproduction of prostaglandin and IL-10 [17 18] and T celldysfunction [18 19 23] For example inhalation of CNTs (031 or 5mgm3 6 hday 14 days) hardly induced injury in lungsbut resulted in nonmonotonic systemic immunosuppression

BioMed Research International 3

Table1Im

mun

omod

ulationof

vario

usnano

particlesinnano

medicinea

pplications

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Carbon

nano

tube

MWCN

TL5ndash15120583m

Inhalatio

n5m

gm

3

6hday

14days

Immun

osup

pressio

nTG

F120573uarrIL-10uarr

MaleC

57BL

6[1718]

D10ndash

20nm

SWCN

TL1ndash3120583

mPh

aryn

gealaspiratio

n40

80120120583gmou

seInflammation

immun

osup

pressio

nTN

F-120572uarrIL-6uarrM

CP1uarr

FemaleB

ALB

candC5

7BL6

[19]

D1ndash4

nm

MWCN

TLseveral120583

mOroph

aryn

gealaspiratio

n1

2and4m

gkg

Inflammation

IL-33uarrC

CL3uarrC

CL11uarr

C57B

L6

[2021]

D125ndash25

nm

MWCN

TLseveral120583

mOroph

aryn

gealaspiratio

n4m

gkg

Inflammation

IL-33uarrIL-5uarrIL-8uarrIL-13uarr

C57B

L6

[22]

D125ndash25

nm

MWCN

TL15plusmn5120583m

Intravenou

sly1m

gkg

Inflammation

IL-4uarrIL-33uarr

C57B

L6

[23]

D25plusmn5nm

MWCN

TL50120583m

Subcutaneous

00503and

05m

gtimes2mou

seAc

uteinfl

ammation

IL-17uarrIL-1120573uarrIL-1120572uarr

IFN-120574uarr

BALB

c[24]

D20ndash

30nm

MWCN

TL03ndash50120583m

Inhalatio

n100m

gm

3times6h

Hypersensitivity

PDGF-AAuarrT

GF-120573uarr

Allergicasthmam

ice

(C57BL

6)

[25]

D30ndash

50nm

SWCN

TL3ndash30120583m

Intratracheal2550120583gtimes

6mou

seHypersensitivity

IL-4uarrIL-5uarrIL-13uarrIFN

-120574uarr

IL-17AuarrIL-23uarrIL-33uarr

Allergicinflammationmice

(maleICR

)[26]

D67n

mGraph

ene

Graph

ene

4plusmn1120583m

2area

Intravenou

sly1m

gkg

Activ

ateTh

2im

mun

erespon

seIL-33uarrIL-5uarrIL-13uarr

C57B

L6

[23]

2plusmn1nm

thick

Fullerene

C60

NA

Intravenou

sly50

ngm

ouse

Immun

osup

pressio

nSerum

histam

inedarrLyndarr

SykdarrR

OSdarr

MC-

depend

entm

odelof

anaphylaxis(C5

7BL6)

[16]

C60

NA

Intra-artic

ular

treatment

100120583Mw

eektimes8week

Immun

osup

pressio

nTN

F-120572darrIL-1120573darr

Ratm

odelof

arthritis(fe

male

Sprague-Daw

leyrats)

[27]

C60

NA

Instillatio

n2m

gkg

Inflammation

IL-1uarrT

NF-120572uarrIL-6uarrIL-12uarr

IFN-120574uarr

MaleICR

[2829]

Carboxyfullerene

NA

Periton

eum

andairp

ouch

40mgkg

Activ

ateimmun

esyste

mNA

C57B

L6

[30]

HydroxylatedC6

0NA

Intraperioneallyinjection

2120583gg

Immun

osup

pressio

nIL-11uarrelasta

se2genedarr

Fatheadminno

w[31]

C60

NA

Intraperito

nealinjection

05m

Ltimes10120583gmLtimes14

days

Immun

osup

pressio

nIFN-120574uarr

Tumor-bearin

gmice

(C57BL

6)

[14]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Goldnano

particles

PfMSP-1

19PvM

SP-1

19coated

GNPs

form

ulated

with

alum

17nm

Subcutaneously25

120583gmou

seIm

mun

ogenic

Antibod

ytiteruarr

BALB

c[15]

PfMSP-1

19PvM

SP-1

19coated

GNPs

17nm

Subcutaneously

25120583gmou

sePo

orim

mun

ogenic

NA

BALB

c[15]

Short-c

hain

PEG

mixed-m

onolayer

protectedgold

cluste

rslt5n

mSubcutaneouslyinjection

40120583Mtimes200120583

LIm

mun

ogenic

Antibod

ytiteruarr

BALB

cAnN

Hsd

[3233]

PEGcoated

GNP

13nm

Intravenou

sly0017085

or426

mgkg

Acuteinfl

ammation

MCP

-1C

CL-2uarr

MIP-1120572C

CL-3uarrM

IP-1120573uarr

RANTE

SCC

L-5uarrIL-1120573uarr


TNF-120572uarr

BALB

c[34]

GNPfunctio

nalized

with

2-mercaptoethanesulfonica

cid

(MES

)orN

NN-

trim

ethylammon

iumethanethiol

(TMAT

)

15nm

Mediaexpo

sure

0016ndash

250p

pm

Activ

ateimmun

erespon

seInflammatory

respon

se

Il-5darrIL-12darrIL-15darrIL-18darr

Zebrafish

embryos

[35]

Citrate-stabilizedGNPs

40nm

Oroph

aryn

gealaspiratio

n08m

gkg

Hypersensitivity

MMP-9uarrM

IP-2uarrT

NF-120572darr

IL-6darr

TDI-sensitisedmice(BA

LBc)

[36]

GNP

21nm

Intraperito

neallyinjection

785120583

gg

Antiflam

matory

TNF-120572mRN

AdarrIL-6mRN

Adarr

MaleC

57BL

6[37]


5nm

100n

molAu

kg

Antiflam

matory

IL-1120573darr

IL-1120573mod

elmice(male

C57B

L6)

[38]

Silver

Nanop

articles

AgN

P2218plusmn172nm

Inhalatio

n191times107particlescm

3times

6hdaytimes5daysw

eektimes2

weeks

Immun

osup

pressio

nMalt1genedarrSem

a7ag

enedarr

C57B

L6

[39]

AgN

P5225plusmn2364nm

Intratrachealinstillatio

n35

or175m

gkg

once

every2

days

for5

weeks

Enhanceimmun

efunctio

nIL-1uarrIL-6uarrT

NF-120572uarrG

SHdarr

T-SO

DdarrM

DAuarrN

Ouarr

Wistar

rats

[40]

Agconjugated

tocore

nano

beads40

ndash50n

mIntradermally

Immun

ogenic

IFN-120574uarrantibod

yuarrH-2Kb

C57B

L6

[41]

Magnetic

Nanop

articles

Iron

Oxide

NP

43nm


n(4

or20120583gtimes3)

Activ

ateimmun

erespon

seIFN-120574uarrIL-4uarr

OVA

-sensitized

mice

(BALB

c)

[4243]

Iron

Oxide

NP

587nm

Intravenou

slyle10mg

ironkg

Immun

osup

pressio

nIFN-120574darrIL-6darrT

NF-120572darr

DTH

mice(maleB

ALB

c)

[44]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Iron

Oxide

NP

35plusmn14nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

OVA

-sensitized

mice

(BALB

c)

[45]

Intratracheally

4times100120583gmou

seHypersensitivity

IgEuarr

IL-4uarr

147plusmn48nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

Intratracheally

4times100120583gmou

seNosig

nificanteffect

NA

Nanoceria

Nanoceria

D8

nmOroph

aryn

gealinstillatio

nof

1030or

100120583

gmou

seInflammation

TNF-120572uarrIL-6uarroste

opon

tinuarr

C57B

L6

[46]

A44m

2 g

Nanoceria

20nm

Sing

leintratracheal

instillationat015ndash7

mgkg

Inflammation

NOdarrIL-12uarr

Specificp

atho

gen-fre

emale

Sprague-Daw

ley(H

la

SD-C

VF)

rats

[47]

Nanoceria

D20ndash

30nm


nat

50and150m

2 mou

seInflammation

IL-1120573uarr

FemaleW

istar

rats

[48]

A241m

2 g

Nanoceria

D55n

mInhalatio

nof

641m

gm

3for

24h48

hand14

days

Inflammation

IL-1120573uarrT

NF-120572uarrIL-6uarr

MDAuarrG

SHdarr

Wistar

rats

[49]

A30ndash

50m

2 g

Quantum

Dots

CdT

eNP

NA

164and

8mgLfor2

4hIm

mun

osup

pressio

nNA

Elliptio

ncomplanata

[50]

CdS

CdT

eNP

NA

510

and20

nmfor9

6hIm

mun

osup

pressio

nNA

Juvenilerainbo

wtro

ut[51]

SilicaN

anop

articles

Amorph

oussilica

NP

30and70

nmIntraperito

nealinjectionof

1mgmice

Inflammation

IL-5uarrIL-6uarrM

CP-1uarr

keratin

ocytec

hemoattractantuarr

FemaleB

ALB

c[52]

Amorph

oussilica

NP

mod

ificatedwith

carboxyl

grou

ps70

nmIntraperito

nealinjectionof

1mgmice

Supp

ressionof

inflammation

NA

Non

porous

nano

silicaN

P15nm

Intravenou

sinjectio

nsat

singled

osea

t50m

gkg

Inflammation

oxidatives

tress

ROSuarrT

NF-120572uarrN

Ouarr

MaleS

Drats

[53]

Polymer

Polysty

rene

NP

50nm

Intratracheal

administratio

nof

200120583

gmou

se

Anti-infl

ammation

immun

osup

pressio

nIL-4darrIL-5darrIL-13darr

Allergen

challengem

ice

[54]

Polysty

rene

beads(PS

B)coup

led

with

theimmun

odom

inant

myelin

proteolip

idprotein

PLP 139ndash151epito

pe(PLP139ndash151-PSB

)

500n

mintravenou

sinjectio

nof

approxim

ately9times109

microparticles

T-celltolerance

IL-17darrINF-120574darr

Peptide-indu

cedexperim

ental

autoim

mun

eenceph

alom

yelitisSJLJm

ice

[55]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Dendrim

er

Pan-DR-bind

ingepito

pe(PADRE

)-deriv

atized-dendrim

er(PDD)

NA

Intravenou

sinjectio

nwith

625

mgkgday

ofLA

mBat

aratio

of101

(PDDLAmB)

for10days

enhanced

adaptiv

eim

mun

ityIFN-120574uarr

FemaleB

ALB

cmice

inoculated

intraperito

neally

with

metacyclic

prom

astig

otes

ofLmajor

[56]

LipidNanop

articles

cSLN

-pDNA(a

DNAvaccine

harbou

ringtheL

donovaniA

2antig

enalon

gwith

Linfantum

cyste

inep

roteinases)com

plexes

241plusmn12nm

immun

ized

inthe

right-hindfootpadwith

50120583gof

Qiagenpu

rified

pDNA

Enhanced

immun

ityRa

tioof

IFN-120574

IL-10uarr

Linfantum

prom

astig

otes

challenged

femaleB

ALB

cmice

[57]

MPL

AN

LP6ndash

25nm

intraperito

nealinjection

ionof

151020120583

gmou

seEn

hanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

CpGN

LPconstructs

6ndash25

nmintraperito

nealinjection

ionof

102040

or80120583gmou

se

Enhanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

Pegylated

liposom

aldo

xorubicin

(Doxil)

85ndash100

nmInfuse

inaccordance

with

thea

dministratio

nguidelineo

fDoxil

Hypersensitivity

reactio

nsoccurred

in45of

patie

nts

NA

Patie

ntsw

ithsolid

tumors

(119899=29)treated

with

Doxilfor

thefi

rsttim

e[59]


(reduced T-cell-dependent antibody against sheep erythro-cytes and T-cell proliferative ability and decreased naturalkiller cell activity) This suppression was accompanied byincreased spleen gene expression of interleukin-10 (IL-10)which is an anti-inflammatory cytokine and NAD(P)H oxi-doreductase [17] Other studies showed that pharyngeal aspi-ration of SWCNTs (40 120583gmouse) in BALBc mice inducedpulmonary inflammation and suppressed the responsivenessof T cell 7 days postexposure This immunosuppression wasassociated with the direct effects of SWCNTs on DCs [19]

312 Fullerene As a strong free-radical scavenger [79]fullerene has anti-inflammatory effects The antioxidativeanti-inflammatory activities of novel fullerenes have beenreported [80] Fullerene could suppress Ag-driven type Ihypersensitivity when human MCs and peripheral bloodbasophils were preincubated with C

60fullerenes This sup-

pression involved decreasing the level of reactive oxygenspecies (ROS) [16] In aMC-dependentmodel of anaphylaxisfullerenes prevented the release of histamine [16] In addi-tion polyhydroxylated fullerene derivatives might protectagainst oxidative stress in ischemia-reperfused lungs [81]C60

also suppressed the tumor necrosis factor alpha (TNF-120572) induced production of proinflammatory cytokines in vitroand inhibited the arthritis in vivo [27] Other studies indifferent animalmodels also showed the immunosuppressioneffects of fullerenes For example hydroxylated fullerenescould interfere with the innate immune system in fatheadminnow [31] Nanocrystalline fullerene showed cytotoxicityand promotive effects on tumor cell growth in vitro and invivo respectively which might be due to the suppression ofanticancer immune response of mice by fullerene [14]

313 Gold NPs The anti-inflammatory properties citrate-coatedGNPswere also reported Citrate coatedGNPs (21 nm)did not cause detectable organ or cell toxicity in mice [37]Studies also indicated that citrate-stabilized 5 nm and 15 nmGNPs inhibited cellular responses induced by interleukin 1beta (IL-1120573) and showed anti-inflammatory activity [38]

314 Silver NPs The studies on the immunotoxicity ofAgNPs are very limited AgNPs induced ROS and inflamma-tion [82 83] indicating its potential interference of immunesystem AgNPs (22 nm) exposure caused the downregulationof expression of Malt1 and Sema7a genes which were associ-ated with immune cell function followed by aberrant T celldifferentiation [39]

315 Magnetic NPs Some in vitro studies showed that ironoxide NPs did not induce inflammatory response on humanmonocyte-macrophages [84] and aortic endothelia cells [85]However high doses of iron oxide NPs may induce oxidativestress [86] When treated with PVA-coated SPION humanmonocyte-derived DCs showed a decreased antigen process-ing and CD4 (+) T cell stimulation capacity [87] Thesestudies suggested the potential immune impact of magneticNPs The immunomodulation of the iron oxide NPs wasmuch more complex in vivo Intratracheally administration

of high dose (4 times 500 120583gmouse) and intermediate dose (4 times250 120583gmouse) of iron oxide NPs with a diameter of 35 plusmn14 nm or 147 plusmn 48 nm inhibited the allergic Th2-dominatedresponse induced by ovalbumin (OVA) The low dose (4 times100 120583gmouse) of iron oxide particles (147 plusmn 48 nm) hadno significant effect while the low dose (4 times 100 120583gmouse)of particles (35 plusmn 14 nm) had an adjuvant effect on theTh2 response to OVA [45] A single intratracheal instillation(250 375 or 500120583gmouse) or four-time repeated instillation(500120583gmouse times 4) showed that both NPs induced lunginflammation and decreased pulmonary immune responsesagainst sheep erythrocytes In another study intravenouslyadministration of iron oxide NPs (587 nm) in doses le 10mgironkg shifted the Th1Th2 immunobalance towards theTh2-dominant direction and suppressed the delayed-typehypersensitivity in OVA-sensitized mice [44] Furthermorerepeated instillations resulted in a reduction of inflammationthan single instillation [88]

316 CeO2NPs Due to their reducibility cerium oxide NPs

(nanoceria) were found to have the ability to reduce ROSandmay be used as a novel therapeutic tool for inflammationtreatment [73] Some in vitro studies indicated that nanoceriawith a small diameter caused a significant anti-inflammatoryeffect [73 89 90] For example nanoceria with a diameterof 3ndash5 nm scavenged free radicals inhibited inflammatorymediator production in J774A1 the murine macrophages[73] A recent study reported that the same size of nanoceriainducedAPCs to secrete IL-10 and induced aTh2-dominatedT cell proliferation The nanoceria (5ndash8 nm) showed aneffective antioxidant property in cardiac progenitor cells andprotected the cardiac progenitor cells from H

2O2-induced

cytotoxicity In addition in vivo investigation on immunecells of the sea urchin indicated that nanoceria suppressed theinnate immunity when force-fed 1mL 10minus2 gL 50ndash60 nm ofnanoceria [91]

317 Quantum Dots As efficient energy donors [92] QDscan induce the generation of ROS by transferring energyto nearby oxygen molecules In vitro studies have shownthat QDs induced production of ROS and led to multipleorganelle damage and cell death [93 94] Preexposure toa dose at 10minus7 to 10minus3 120583gmL CdTe QDs suppressed theimmune responses of J774A1 macrophage to bacteria byreducing NO TNF-120572 KCCXCL-1 and IL-8 production[95] These in vitro studies suggested that QDs might havehigh immunotoxicity In vivo studies also showed similarresults CdTe QDs (16 4 and 8mgL for 24 h at 15∘C)significantly decreased the viability of hemocytes as wellas number of hemocytes capable of ingesting fluorescentbeads in Elliption complanata mussels [50] The immuno-suppression was also observed in Juvenile rainbow troutWhen 5 10 and 20 nM CdSCdTe QDs were exposed toJuvenile rainbow trout for 96 h at 15∘C the leukocyte countsviability and both resting and active phagocytic activity weresignificantly reduced [51] QDs affected the proliferation ofimmune cells but did not induce immune response includingcytokine production [96] Size of QDs aggregates may affect


the immune response of QDs Large CdSCdTe QDs aggre-gates (25ndash100 nm) reduced phagocytosis more than smallerNPs (lt25 nm) on bivalves (Mytilus edulis and Elliptio com-planata) and fish (Oncorhynchus mykiss) [97] Thereforecaution is needed to overcome this barrier when QDs areapplied in clinical treatment

318 Polymeric NPs In vivo studies indicated that somepolymeric NPs inhibited inflammation but had no effect onhost immunity [54 98] NPs produced by particle replicationin nonwetting template technology remained in the lungs forup to 7 days without triggering host immunity after intra-tracheal administration of 50 120583gmouse [98] PolystyreneNPs (50 nm) inhibited lung inflammation by intratrachealadministration of 200120583gmouse after allergen challengeThisinhibition was due to the modulation of DCs functions NPsinhibited expansion of CD11c+MHCIIhi DCs in the lungs anddraining lymph node and allergen-laden CD11bhiMHCIIhiDCs in the lungs [54] In addition polystyrene particles havethe potential to halt the disease process in autoimmunityFor example antigen-decorated polystyrene particles with adiameter of 500 nm induced T-cell tolerance and amelioratedexperimental autoimmune encephalomyelitis by inactivatingpathogenic T cells [55]

32 Immunostimulation

321 CarbonNanotubes CNTs induced immunostimulationin vitro and in vivo The oropharyngeal aspiration of MWC-NTs (1 2 and 4mgkg) in C57BL6 mice induced inflam-mation (30 days postinstillation) in lungs [20 21] MWCNTswere translocated progressively into the spleen reached amaximumof 48 h after intraperitoneally (ip) administrationwhich caused the lymphocytic hyperplasia and increasedoxidative stress in the spleen [99] Subcutaneous adminis-tration of MWCNTs with total dose of 10mg for two scinjections in BALBc mice induced acute immunologicalreactions for 1 week (activation of complement and increasedproinflammatory cytokines) However the accumulation ofMWCNTs and injury was not observed in spleen [24]MWC-NTs injected intravenously activated Th2 immune responseby elevating Th2 cytokines and increasing number of CD4+and CD8+ T cell in the spleen [23] In other studies CNTsshowed allergy adjuvant effect in inflammatory mass Forexample SWCNTs andMWCNTs exhibited adjuvant activityto the OVA-sensitized mice [25 100] MWCNTs aggravatedasthma and induced fibrosis in OVA-sensitized lungs butshowed no response with healthy pulmonary The resultsindicated that these NPs could bring harm to asthma patientsbut not health ones [25] In recent in vitro studies MWCNTsincreased the release of a series of cytokines in peripheralblood mononuclear cells (PBMCs) from healthy donorsafter stimulation with toll-like receptor (TLR) agonists orT cell mitogen However MWCNTs suppressed immuneresponses in PBMCs frommite-allergic subjects These stud-ies suggest that MWCNTs may either stimulate or suppressimmune system depending on their immune cell target[101]

322 Graphene GO could induce healthy DCs to differen-tion and maturation at varying degrees [102] but suppressthe antigen-delivering ability of OVA-loaded DCs to Tlymphocytes [103]This inhibitionwas associatedwith down-regulation of subunit LMP7 of immunoproteasome in cellswhich is responsible for antigens processing in DCs [103]Whenmacrophage cells RAW2647 were incubated with GOtoll-like receptor (TLR4TLR9-) 6 modulated autophagy andinflammatory responses occurred [104] In addition PVP-coated GO exhibited lower immunogenicity than GO on theaspect of inducing maturation and differentiation of DCs[102] PVP-coated GO enhanced the physiological activityof macrophages which showed anti-phagocytosis abilityagainst macrophages and delayed the apoptotic process ofT lymphocytes [102] This advantage makes PVP-coated GOa promising candidate of immunoadjuvant The effect oftwo sizes (2120583m and 350 nm) of the GO in response tomicrophages was investigated [105] These two NPs hadequal uptake amount in macrophages but microsized GOinduced stronger inflammation responses and showed diver-gent intracellular locations compared to nanosized GO [105]This result demonstrated that lateral dimension of GO playsan important role in the regulation of cellular responsesRecent studies demonstrated that intravenously deliveredgraphene nanosheets induced site-specificTh2 inflammatoryresponses in the lungs via the IL-33ST2 axis [23] Thiseffect may cause host defense and exacerbation of allergicdiseases However more studies in vivo are needed to assessand eliminate the potential immunomodulation of graphene-based materials to ensure their safety for applications inbiomedicine

323 Fullerene Some studies showed that C60have immun-

ostimulatory properties [28ndash30 103 106] After instillationC60upregulated gene expression of various proinflammatory

cytokines (IL-1 TNF-120572 IL-6) andTh1 cytokines (IL-12 IFN-120574) in mice Besides inflammation C

60could activate the

immune system The carboxyfullerene could prolong theinfiltrating neutrophils to enhance the bactericidal activity ofneutrophils [30] Other studies indicated that fullerene mayenhance the ability of DCs to stimulate T cells and further-more activated cells of innate immune system by enhancingproduction of IL-6 and an activation of natural killer (NK)cells [103 106] In addition immunization of mice with aC60

fullerene derivative conjugated to bovine thyroglobulincould produce a population of fullerene-specific antibodieswhich included a subpopulation that cross-reacted with a C

70

fullerene [29]

324 Gold NPs GNPs with different surface modifica-tion showed different immunogenicity in organisms Theimmunogenicity of GNPs coated with C-terminal 19 kDafragment of merozoite surface protein 1 (MSP-1

19) was an

important vaccine candidate In this study GNPs showedpoor immunogenicity in mice but enhanced antibodyresponse when formulated with alum [15] However GNPscoated with monosaccharide or disaccharides could initiatethe immune response by activating the macrophages [107]


Some studies indicated that high concentrations of PEGcoated on GNPs could induce antibody production andtrigger immune responses High doses of injected PEG-coated GNPs were cleared through these mechanisms [3233]

GNPs can also induce inflammatory responses in vivoWell-dispersed PEG-coated GNPs (13 nm) can be recognizedby host defense mechanism and induce acute inflammationand apoptosis in the liver [34] If inflamed tissues are exposedstronger immune responses may be induced [108] Whenexposed to sensitized mice 40 nm GNPs could lead to athreefold increase in airway hyperreactivity and increase thenumber of neutrophils and macrophages [36]

325 Silver NPs Intratracheal instillation of AgNPs with adiameter of 5225 plusmn 2364 nm could enhance the respiratoryimmune function through oxidative stress and inducedinflammation in the respiratoryWhen alveolar macrophageswere activated by AgNPs to cause phagocytosis the alve-olar macrophages generated ROS and free radicals whichresulted in oxidative stress The normal function of alveolarmacrophages and epithelial cells was subsequently affectedThis led to oversecretion of cytokines and oxides which thencaused the stimulation of the respiratory immune function[40] These opposite results may be due to the differentdiameters of NPs Covalent conjugation of Ag to solid corenanobeads with different diameters ranging from 002 to2 120583m was found localized into DCs (DEC205+ CD40+CD86+) in draining lymph nodes and induced high levels ofIFN-120574 production and high antibody titers in tumor-bearingmice [41]

326 CeO2NPs Instillation of 100 120583g nanoceria with a

diameter of 8 nm in C57BL6 mice revealed that the NPsinduced inflammation in pulmonary system by activatingMCs [46] Other studies using bigger sizes showed the sameeffect Single intratracheal instillation of 20 nm nanoceriaat 015ndash7mgkg caused a dose-dependent inflammation andlung injury [47] The intratracheal instillation of 20ndash30 nmnanoceria (241m2g) with doses of 50 and 150 cm2mouseinduced both acute and chronic neutrophilicmildly cyto-toxic inflammation [48] Inhalation of 55 nm nanoceriawith an average aerosol concentration of 641mgm3 for 4 hinduced cytotoxicity via oxidative stress and led to a chronicinflammatory response including up regulation of IL-1120573TNF-120572 and IL-6 [49]

327 Silica NPs 30 nm amorphous silica NPs were inves-tigated in PBMCs and purified monocytes These NPscould induce inflammatory response as production of IL-1120573 IL-8 and ROS This result indicated the potential ofsilica NPs to evoke innate immune reactions [109] Otherreports showed that 30 and 70 nm silica NPs inducedhigher production of TNF-120572 in RAW2647 cells and strongerinflammatory responses (IL-5uarr IL-6uarr MCP-1uarr keratinocytechemoattractantuarr) than 300 and 1000 nm particles in vivo

through intraperitoneally injection The 70 nm particle-induced TNF-120572 production was dependent on the produc-tion of ROS and activation of mitogen activated proteinkinases (MAPKs) However modification of carboxyl groupson 70 nmparticles dramatically suppressed the inflammatoryresponses [52] As well Kupffer cells stimulated by 15 nmsilica NPs released large amounts of ROS TNF-120572 and NOThe viability of Buffalo rat liver (BRL) cells was reduced aftercultured with silica NP-stimulated Kupffer cells The authorsalso studied the intravenous injections of silica NPs with asingle dose of 50mgkg It caused hepatic inflammation andoxidative stress [53]

328 Polymeric NPs Polymer-based NPs were shown to beeffective adjuvants in vaccination [72 110 111] These poly-mers have the ability to activate cellular immune responsesin the host [112] For example N-trimethyl chitosan-mono-N-carboxymethyl chitosan (TMCMCC) NPs appeared tobe very promising as an adjuvant and delivery system forantigens Intranasal vaccination with tetanus toxoid loadedTMCMCC NPs (2835 plusmn 25 nm) was shown to induceboth the mucosal and systemic immune response (enhancedantibody response) The enhanced immunoglobulin G (IgG)immune response could be explained by the sustained releaseof the toxoid [113]

Some polymer NPs were reported to activate immunesystem through modulating the activation and capabilityof immune cells such as dendritic cells and T cells [114ndash116] Amphiphilic NPs possessed pathogen-mimicking prop-erties by activating DCs similar to lipopolysaccharide (LPS)thus it has the ability to activate innate immune response[114] Poly(methyl vinyl ether-co-maleic anhydride) NPs(149 plusmn 2 nm) activated DCs through TLR stimulation ininnate immune system [115] As well the sulfonate (245 nm)and phosphonate-functionalized (227 nm) polystyrene NPsinduced the maturation of immature DCs and significantlyenhancedT cells stimulatory capacity indicating a shift toTh1response [116]

329 Other NPs Dendrimers have the ability to stimu-late immune system and can be used as potential candi-dates for vaccines [76] Maltose-functionalized dendrimer-peptide complex is a potential DC-based vaccine candi-date by stimulating DC and activating the immune system[117] Research also showed that Pan-DR-binding epitope-derivatized-dendrimer could reduce the effective dose ofliposomal amphotericin B inmurine cutaneous leishmaniasisand enhance adaptive immunity by activating strong parasitespecific T-cell responses [56]

Protein NPs have shown immunostimulating propertiesin recent studies [118ndash120] Self-assembled protein NPs thatdisplayed epitopes of the repeat sequence in circumsporo-zoite protein of plasmodium falciparum (PfCSP) elicited astrong immune response against PfCSP [119 121] In additionprotein NPs mimic viruses have the ability to facilitate DCsactivation and cross-presentationThese proteinNPs codeliv-ered with peptide epitopes to DCs showed an increased andprolonged CD8+ T cell activation [120]


A lipidNPwas investigated in aDNAvaccine applicationThis NP which decorated with stearyl-conjugated KALAan 120572-helical peptide (sequence WEAKLAKALAKALAK-HLAKALAKALKACEA) showed enhancement of transgeneexpression this enhancement was closely related to immune-activation [122] A cationic solid-lipid NP was used as a vac-cine to deliver a DNA vaccine against visceral leishmaniasisHigh levels of IFN-120574 and low levels of IL-10 production weredetected in BALBc mice after administration of the DNAvaccine delivered by this cationic solid-lipid NP This NPinduced a strongTh1 immune response indicating its poten-tial as therapeutic agent against visceral leishmaniasis [57]Nanolipoprotein conjugated with TLR agonists monophos-phoryl lipid A or CpG oligodeoxynucleotides significantlyenhanced the immunostimulatory profiles compared to theagonists alone Moreover the BALBc mice pretreated withCpGnanolipoprotein coloaded nanoconstructs but not CpGalone survived a lethal influenza challenge [58] Researchalso indicated that intravenous injection of liposome-DNAcomplexes elicited production of IFN-120572 and IFN-120573 in vivowhich suggested that the liposome-DNA complexes caninduce inflammation and cause systemic toxicity [123] Inanother study it was reported that Doxil an PEGylatedliposomal formulation of doxorubicin may cause hyper-sensitivity reactions while the standard doxorubicin didnot indicating that liposomes might be responsible for thishypersensitivity [59] It was speculated that the complementsystem activation by Doxil may play a key role in this effect[59]

4 The Factors Affecting Immunomodulationof NPs

Many factors contribute to immunomodulation of NPs Thenature of NPs such as composition surface chemistry sizeshape and protein-binding ability dominates these interac-tions Besides individual difference and exposure route alsocontribute to immunomodulation of NPs

41 Composition Composition of NPs lays a vital role inthe interactions between NPs and immune system Forexample QDs showed high immunotoxicity [50 51] becausethey release heavy metal ions Some other NPs exhibit lessimmunotoxicity [17 23 39 44 54] immunogenic [15 32]or no effect [45] The different core of NPs gave differentreaction in allergy mass For example CNTs and GNPsshowed adjuvant effect and led to hypersensitivity in theseallergy masses [25 26 36] while fullerene often showedimmunosuppression [14 31]

42 Surface Chemistry For NPs with the same compositionsurface properties may also affect the immune system Engi-neered NPs such as CNTs fullerenes GNPs and silica NPscan be modified with diverse surface chemistry This mayalter their immune response both in vitro and in vivo

Eighty diversely functionalized multiwall nanotube(MWNT) induced different levels of protein bindingcytotoxicity and immune responses (Figure 2) [124] The

modification of MWCNTs significantly alleviated nuclearfactor kappa B (NF-120581B) activation and reduced immuno-toxicity ofMWCNTs in BALBcmice [125] Carboxyfullereneactivated immune system of C57BL6 mice by prolongingthe infiltrating neutrophils to enhance the bactericidalactivity of neutrophils [30] while hydroxylated fullerenesinterferedwith the innate immune system in fatheadminnow[31] MWCNTs-PEG induced less generation of ROS andcytotoxicity in macrophages than MWCNTs-COOH whichwas in correspondence with the lower cellular uptake ofMWCNTs-PEG [126] The monolayer-protected GNPs invivo were studied Simple place-exchange reactions withinthe monolayer by short chain mercaptotetraethylene glycolhave been used The short chain at lower concentrations didnot trigger the immune system to produce anti-PEG antibody[33] However high concentration mixed monolayer coatedNPs initiated an immune response [32] Silica NPs (70 nm)induced strong inflammation by intraperitoneal injectionbut these inflammatory responses could be dramaticallysuppressed by surface modification by carboxyl groups [52]The toxicity of porous silica NPs to immune cells was surfacechemistry and surface charge-dependent Compare tosurface hydrophobicity surface charge had stronger impacton NPsrsquo immunotoxicity in vitro and in vivo Positivelycharged hydrophobic NPs showed more DNA damage thannegatively charged hydrophilic NPs [127]

43 Size Size is another important parameter that deter-mines the interaction with organisms When examinedimmunity is induced by a series of differentially sized (2040 49 67 93 101 and 123 nm) polystyrene nanobeads IFN-120574 induction from CD8+ T cells was limited to 40 and 49 nmbeads while 93ndash123 nmbeads inducedCD4+ T cell activationand increased IL-4 levelThese results showed that the size ofnanobead for vaccination could influence the type 1type 2cytokine balance This would be useful in the developmentof vaccines against common human pathogens [128] 200 nmNPs increased more antigen-specific polyfunctional CD4+ Tcells as compared to 30 nm NPs The immunoactivity of dis-accharides coated GNPs is strongly dependent on size Theyused 2 and 5 nm GNPs coated with disaccharides These NPsactivated the macrophages and induced the proliferation of Tcells and the increase of IL-2 levels The 5 nmNPs performedfar better than 2 nmones (increasedAPC proliferationMHCII expression T cell proliferation and IL-2 expression) [107]Other researches indicated that single instillation (250 375or 500 120583gmouse) of 35 plusmn 14 nm iron oxide NPs inducedhigher levels of inflammation and immunodepression than147plusmn48 nm ones [88] Repeated intratracheal administrationof high dose (4 times 500120583gmouse) and intermediate dose (4 times250 120583gmouse) of the same NPs inhibited the allergic Th2-dominated response induced by OVA The low dose (4 times100 120583gmouse) of 147 plusmn 48 nm iron oxide particles had nosignificant effect but the low dose (4 times 100 120583gmouse) of 35plusmn14 nm particles had an adjuvant effect on theTh2 response toOVA [45] Aggregate size may also affect the immunotoxicityof QDs The toxicity of CdSCdTe QDs was size dependentLarge CdSCdTe QD aggregates (25 nmndash100 nm) reduced


OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)

Figure 2 Multiassay score of the functional MWNT library (a) Surface molecular compositions of combinatorial MWNT library members(b) Findings from four protein (BSA carbonic anhydrase chymotrypsin and hemoglobin) binding assays cytotoxicity and immune responseassays (MWNT-induced NO release) at 50 120583gmL in THP-1 macrophages were ranked for all library members The sum of their ranks wasdesignated the multiassay score and is shown as vertical bars in the graph Reprinted with permission from [124]


phagocytosis of fishmacrophagesmore than did smaller ones(lt25 nm) [97]

44 Protein Binding When NPs enter the body throughinjection they firstly interact with blood [129] The plasmaprotein binding on the NPs surface such as apolipoprotein Eand transferrinmay contribute to the activationdeactivationof receptor-dependent signaling [130]

The amount and types of proteins adsorbed on the NPsaffect the interactions of cells and NPs and the biologicalresponses [131 132]The composition surface characteristicsand shape of NPs affect the manners that the proteinsbind to them [129 133ndash136] The blood proteins adsorbedonto the NPs include immunoglobulins apolipoproteins andproteins of the complement system among many othersThese proteins may act as signals for immune responses [137138] Furthermore NPs may induce conformational changesin the structure of adsorbed proteins Negatively chargedpoly(acrylic acid-) conjugated GNPs bound with fibrinogenand induced the unfolding of this protein which promotedinteraction with Mac-1 an integrin receptor This activationincreased the NF-120581B signalling pathway and released inflam-matory cytokines [139]

45 Exposure Route Exposure route is another factor affect-ing the immunomodulation ofNPsTheoutcomes of immuneresponse are dependent on entrance of NPs In the lungsDCs pulmonary epithelium and macrophages play animportant role in handling foreign materials In the bloodleukocyte such as neutrophil eosinophil basophil lympho-cyte and monocyte play a vital role Single intratrachealinstillation of 500120583gmouse iron oxide NPs (35 plusmn 14 nmand 147 plusmn 48 nm) induced lung inflammation and decreasedpulmonary immune responses against sheep erythrocytes[88] Pharyngeal aspiration of SWCNTs modified systemicimmunity by modulating DCs function [19] Intravenouslyadministration of iron oxide NPs (587 nm) could sup-press the infiltration and functional activity of Th1 cellsand macrophages [44] Intravenous injection of graphenenanosheets activated a Th2 immune response which con-sisted of neutrophilic influx and a significant increase inIL-5 IL-13 IL-33 in the bronchoalvelar lavage fluid [23]The dosage of administration is also important Intratrachealinjection of iron oxide NPs (35 plusmn 14 nm) inhibited theallergic response in OVA-sensitized mice at a dosage of 4 times250120583gmouse or 4 times 500 120583gmouse but showed adjuvanteffect at a dosage of 4 times 100 120583gmouse [45]

5 The Mechanisms of ImmunomodulationInduced by NPs

NPs interact with both innate and adaptive immune cellsaffect their functions and disturb immune system (Figure 3)

Inflammation is an important response of immune sys-tem which can be induced by NPs evidenced by the pro-duction of cytokines or chemokines Oxidative stress causedby NPs is reported to be the main downstream events ofthe inflammation NPs have large surface areas and strong

TLR pathwayNF-120581B

Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10

Immediatehypersensitivity

Delayed type hypersensitivity

IFN-120574

CD4 T cell

APC (DCs Macrophages

Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )

Figure 3 Mechanisms involved in NPs-induced immunomodu-lation The stimulationsuppression to immune system dependson the nature of NPs and results in different outcomes NPsnanoparticles NF-120581B nuclear factor kappa B TLR pathway toll-like receptor pathway APC antigen-presenting cell DCs dendriticcells MCs mast cells GM-CSF granulocyte-macrophage colony-stimulating factor Th0 type 0 T-helper lymphocyte Th1 type1 T-helper lymphocyte Th2 type 2 T-helper lymphocyte solidline with arrow activatereleaseinduce solid line with verticaldashes at ends inhibit dotted line possible influence broken linepolarizationdifferentiation

oxidative abilities than normal particles [140] Oxidativedamage induced by NPs is an important factor of immuneimbalance [11] Many types of NPs have been shown toproduce ROS in vitro and in vivo and enhance immunefunction or inflammatory response [40 49 53 86 141] Freeradical-induced tissue damage plays an important role ininflammatory diseases [142 143]

The signal pathway to induce ROS and mediate inflam-mation was reported Among them TLR4 signaling pathwaywas documented GO could induce intracellular ROS whichdecreased the viability of macrophages and induced necrosisby a TLR4 signaling pathway (Figure 4) [144] TLR is areceptor of the innate immune system and innate immunitycould be triggered by stimulating TLRs and lead to strongadaptive immunity [115] Activation of the TLR pathwayscould induce chronic inflammation and ROS [145] Resentresearch indicated that quantum dots could activate myeloiddifferentiation primary response gene 88 (MyD88 which isan adapter protein to activate NF-120581B) dependent-TLRs inmcrophages and activated NF-120581B [146]

NF-120581B pathway is another key regulator of immuneresponse [125 147ndash149] As an important regulator of proin-flammatory gene expression synthesis of cytokines suchas IL-1120573 IL-6 IL-8 and TNF-120572 is mediated by NF-120581B


Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK

Myosin heavy chainMyosin light chain

Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO

Figure 4 A schematic diagram elucidating the mechanisms responsible for GO-induced cytotoxicity to macrophages Reprinted withpermission from [144]

Activation of NF-120581B may induce human inflammatory dis-eases [150 151] It was reported that negatively chargedpoly(acrylic acid-) conjugated GNP activated the NF-120581Bsignalling pathway in THP-1 cells The cells released inflam-matory cytokines including TNF-120572 and IL-8 [139] Andcitrate-stabilized 10 nm GNPs could induce activation of anNF-120581B regulated luciferase reporter in murine B-lymphocytecell line (CH12LX) and altered the cell function [152]

NPs may also disturb the immune balance by inappro-priate maturationactivation of APCs such as DCs [26 153]Intratracheal instillation of 43 nmMIONs the alveolar regionof BALBc mice could generate a significant number ofexosomes These exosomes were quickly eliminated from thealveolar region into systemic circulation and transferred theirsignals to the immune system which resulted in maturationof DCs and activation of splenic T cells and the exosome-induced T-cell activation is more efficient in OVA-sensitizedmice [42 43] Cytotoxicity to immune cells may contribute toimmunosuppression of NPs QDs may decrease the viabilityof hemocytes in Elliption complanata mussels [50] andreduced phagocytosis on bivalves and fish [97]

Recent reports indicated that NPs could modulate thehomeostasis of immune cells including the shift of Th1Th2balance [43 44 89] and monocyte homeostasis [154] Forexample magnetic iron oxide NPs activated the T cellsinduced a Th1 polarization and aggravated inflammation[43]Other studies showed that SWCNTs accentuatedThcellsimmunity includingTh2 (IL-4uarr IL-5uarr and IL-13uarr) andTh17

(IL-17Auarr IL-23uarr) The inappropriate maturationactivationof APCs such as DCs might be responsible for these accen-tuated Th cells immunity [26 153] The normal immunesystem keeps a Th1Th2 balance in order to achieve anappropriate immune response Selectively activating Th1 orTh2 cells results in immune deviation and breaks the balanceof immune system In addition MWCNTs could selectivelydecrease phagocytosis-competent monocytes and promoteadhesion of the phagocytosis-incompetent monocytes inblood flow [154]

6 Conclusion

The immune response of NPs is like a double-edged swordin nanomedicine applications by bringing both benefits andharms We should take advantage of the benefits from theimmunomodulating properties of NPs and on the otherhand avoid the undesirable immune responses in order tominimize the systemic side effects The factors affecting theimmune response are complex including particle compo-sition size surface chemistry plasma protein binding andexposure route Investigation of the relationship betweenproperties of NPs and systemic immune response is crucialfor their application in medicine and other areas Althoughtreatments of acute and long-term immune toxicities havebeen developed current approaches of prediction preven-tion and treatment of nanoimmunomodulation are stilllacking encouraging further in-depth studies


Abbreviations

APC Antigen-presenting cellCNT Carbon nanotubeSWCNT Single walled carbon nanotubeMWCNT Multiwalled carbon nanotubeDC Dendritic cellOVA OvalbuminBSA Bull serum albuminTGF-120573 Transforming growth factor betaPBMCs Peripheral blood mononuclear cellsTh cells Helper T cellsIL InterleukinGO Grapheme oxideTRL Toll-like receptorPVP Polyvinyl pyrrolidoneMC Mast cellROS Reactive oxygen speciesTNF-120572 Tumor necrosis factor alphaIFN-120574 Interferon gammaPEG Polyethylene glycolGNP Gold nanoparticleAgNP Silver nanoparticleQDs Quantum dotsPfCSP Circumsporozoite protein of plasmodium

falciparumLPS LipopolysaccharideMCP-1 Monocyte chemoattractant protein-1MAPKs Mitogen activated protein kinasesNF-120581B Nuclear factor kappa BMIONs Magnetic iron oxide nanoparticlesDNA Deoxyribonucleic acidMHC II Major histocompatibility complex class II

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by the National Natural ScienceFoundation of China (21137002 21077068 and 21307077)the Doctoral Fund of the Ministry of Education of China(20130131120007) China Postdoctoral Science Foundationfunded Project (2013M541920) the Natural Science Foun-dation of Shandong Province (ZR2013BQ026) and theNational Key Basic Research and Development Program(973) (2010CB933504)

References

[1] Z Vanic and N Skalko-Basnet ldquoNanopharmaceuticals forimproved topical vaginal therapy can they deliverrdquoThe Euro-pean Journal of Pharmaceutical Sciences vol 50 no 1 pp 29ndash412013

[2] C-K Lim J Heo S Shin et al ldquoNanophotosensitizers towardadvanced photodynamic therapy of cancerrdquo Cancer Letters vol334 no 2 pp 176ndash187 2013

[3] C Corot K G Petry R Trivedi et al ldquoMacrophage imagingin central nervous system and in carotid atherosclerotic plaqueusing ultrasmall superparamagnetic iron oxide in magneticresonance imagingrdquo Investigative Radiology vol 39 no 10 pp619ndash625 2004

[4] C K Kim P Ghosh C Pagliuca Z Zhu S Menichetti and VM Rotello ldquoEntrapment of hydrophobic drugs in nanoparticlemonolayerswith efficient release into cancer cellsrdquo Journal of theAmerican Chemical Society vol 131 no 4 pp 1360ndash1361 2009

[5] X Wang J Li Y Wang et al ldquoA folate receptor-targetingnanoparticle minimizes drug resistance in a human cancermodelrdquo ACS Nano vol 5 no 8 pp 6184ndash6194 2011

[6] R Li R Wu L Zhao M Wu L Yang and H Zou ldquoP-glycoprotein antibody functionalized carbon nanotube over-comes the multidrug resistance of human leukemia cellsrdquo ACSNano vol 4 no 3 pp 1399ndash1408 2010

[7] J M Nam C S Thaxton and C A Mirkin ldquoNanoparticle-based bio-bar codes for the ultrasensitive detection of proteinsrdquoScience vol 301 no 5641 pp 1884ndash1886 2003

[8] H-H Chang J M F Moura Y L Wu and C Ho ldquoAutomaticdetection of regional heart rejection in USPIO-enhancedMRIrdquoIEEE Transactions on Medical Imaging vol 27 no 8 pp 1095ndash1106 2008

[9] K Riehemann S W Schneider T A Luger B Godin M Fer-rari andH Fuchs ldquoNanomedicine challenge and perspectivesrdquoAngewandte Chemie International Edition vol 48 no 5 pp872ndash897 2009

[10] C Janeway P Travers and S Hunt Immunobiology TheImmune System in Health and Disease vol 7 Current Biology1996

[11] S Hussain J A J Vanoirbeek and P H M Hoet ldquoInteractionsof nanomaterials with the immune systemrdquo Wiley Interdisci-plinary Reviews Nanomedicine and Nanobiotechnology vol 4no 2 pp 169ndash183 2012

[12] J Descotes G Choquet-Kastylevsky E van Ganse and TVial ldquoResponses of the immune system to injuryrdquo ToxicologicPathology vol 28 no 3 pp 479ndash481 2000

[13] M A Dobrovolskaia and S EMcNeil ldquoImmunological proper-ties of engineered nanomaterialsrdquo Nature Nanotechnology vol2 no 8 pp 469ndash478 2007

[14] N S Zogovic N S Nikolic S D Vranjes-Djuric et alldquoOpposite effects of nanocrystalline fullerene (C60) on tumourcell growth in vitro and in vivo and a possible role of immunosu-pression in the cancer-promoting activity of C60rdquo Biomaterialsvol 30 no 36 pp 6940ndash6946 2009

[15] S Parween P K Gupta and V S Chauhan ldquoInduction ofhumoral immune response against PfMSP-119 and PvMSP-119using gold nanoparticles along with alumrdquo Vaccine vol 29 no13 pp 2451ndash2460 2011

[16] J J Ryan H R Bateman A Stover et al ldquoFullerene nanomate-rials inhibit the allergic responserdquo Journal of Immunology vol179 no 1 pp 665ndash672 2007

[17] L A Mitchell J Gao R V Wal A Gigliotti S W Burchiel andJ D McDonald ldquoPulmonary and systemic immune response toinhaled multiwalled carbon nanotubesrdquo Toxicological Sciencesvol 100 no 1 pp 203ndash214 2007

[18] L A Mitchell F T Lauer S W Burchiel and J D McDonaldldquoMechanisms for how inhaled multiwalled carbon nanotubessuppress systemic immune function in micerdquoNature Nanotech-nology vol 4 no 7 pp 451ndash456 2009


[19] A V Tkach G V Shurin M R Shurin et al ldquoDirect effects ofcarbon nanotubes on dendritic cells induce immune suppres-sion upon pulmonary exposurerdquo ACS Nano vol 5 no 7 pp5755ndash5762 2011

[20] X Wang P Katwa R Podila et al ldquoMulti-walled carbonnanotube instillation impairs pulmonary function in C57BL6micerdquo Particle and Fibre Toxicology vol 8 no 1 article 24 2011

[21] P Katwa X Wang R N Urankar et al ldquoA carbon nanotubetoxicity paradigm driven by mast cells and the IL-33ST2 axisrdquoSmall vol 8 no 18 pp 2904ndash2912 2012

[22] N Kosaka M Mitsunaga P L Choyke and H Kobayashi ldquoInvivo real-time lymphatic draining using quantum-dot opticalimaging in micerdquo Contrast Media amp Molecular Imaging vol 8no 1 pp 96ndash100 2013

[23] X Wang R Podila J Shannahan A Rao and J Brown ldquoIntra-venously delivered graphene nanosheets and multiwalled car-bon nanotubes induce site-specificTh2 inflammatory responsesvia the IL-33ST2 axisrdquo International Journal of Nanomedicinevol 8 pp 1733ndash1748 2013

[24] J Meng M Yang F Jia Z Xu H Kong and H Xu ldquoImmuneresponses of BALBc mice to subcutaneously injected multi-walled carbon nanotubesrdquoNanotoxicology vol 5 no 4 pp 583ndash591 2011

[25] J P Ryman-Rasmussen E W Tewksbury O R Moss M FCesta B A Wong and J C Bonner ldquoInhaled multiwalledcarbon nanotubes potentiate airway fibrosis in murine allergicasthmardquoTheAmerican Journal of Respiratory Cell andMolecularBiology vol 40 no 3 pp 349ndash358 2009

[26] K-I Inoue E Koike R Yanagisawa S Hirano M Nishikawaand H Takano ldquoEffects of multi-walled carbon nanotubes ona murine allergic airway inflammation modelrdquo Toxicology andApplied Pharmacology vol 237 no 3 pp 306ndash316 2009

[27] K Yudoh R Karasawa K Masuko and T Kato ldquoWater-solublefullerene (C60) inhibits the development of arthritis in the ratmodel of arthritisrdquo International Journal of Nanomedicine vol4 pp 217ndash225 2009

[28] E-J Park H Kim Y Kim J Yi K Choi and K Park ldquoCarbonfullerenes (C60s) can induce inflammatory responses in thelung of micerdquo Toxicology and Applied Pharmacology vol 244no 2 pp 226ndash233 2010

[29] B X Chen S R Wilson M Das D J Coughlin and BF Erlanger ldquoAntigenicity of fullerenes antibodies specific forfullerenes and their characteristicsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 95 no18 pp 10809ndash10813 1998

[30] N Tsao T Luh C Chou JWu Y Lin andH Lei ldquoInhibition ofgroup A streptococcus infection by carboxyfullerenerdquo Antimi-crobial Agents and Chemotherapy vol 45 no 6 pp 1788ndash17932001

[31] B Jovanovic L Anastasova EW Rowe and D Palic ldquoHydrox-ylated fullerenes inhibit neutrophil function in fatheadminnow(Pimephales promelas Rafinesque 1820)rdquo Aquatic Toxicologyvol 101 no 2 pp 474ndash482 2011

[32] C A Simpson B J Huffman A E Gerdon and D E CliffelldquoUnexpected toxicity of monolayer protected gold clusterseliminated by PEG-thiol place exchange reactionsrdquo ChemicalResearch in Toxicology vol 23 no 10 pp 1608ndash1616 2010

[33] C A Simpson A C Agrawal A Balinski K M Harknessand D E Cliffel ldquoShort-chain PEGmixed monolayer protectedgold clusters increase clearance and red blood cell countsrdquo ACSNano vol 5 no 5 pp 3577ndash3584 2011

[34] W-S Cho M Cho J Jeong et al ldquoAcute toxicity and phar-macokinetics of 13 nm-sized PEG-coated gold nanoparticlesrdquoToxicology and Applied Pharmacology vol 236 no 1 pp 16ndash242009

[35] L Truong S C Tilton T Zaikove et al ldquoSurface functional-ities of gold nanoparticles impact embryonic gene expressionresponsesrdquo Nanotoxicology vol 7 no 2 pp 192ndash201 2013

[36] S Hussain J A J Vanoirbeek K Luyts et al ldquoLung exposureto nanoparticles modulates an asthmatic response in a mousemodelrdquo European Respiratory Journal vol 37 no 2 pp 299ndash309 2011

[37] H Chen A Dorrigan S Saad D J Hare M B Cortie and SM Valenzuela ldquoIn vivo study of spherical gold nanoparticlesinflammatory effects and distribution in micerdquo PLoS ONE vol8 no 2 Article ID e58208 2013

[38] V V Sumbayev I M Yasinska C P Garcia et al ldquoGoldnanoparticles downregulate interleukin-1-induced pro-inflam-matory responsesrdquo Small vol 9 no 3 pp 472ndash477 2013

[39] H-Y Lee Y Choi E Jung et al ldquoGenomics-based screeningof differentially expressed genes in the brains of mice exposedto silver nanoparticles via inhalationrdquo Journal of NanoparticleResearch vol 12 no 5 pp 1567ndash1578 2010

[40] H Liu D Yang H Yang et al ldquoComparative study of res-piratory tract immune toxicity induced by three sterilisationnanoparticles silver zinc oxide and titanium dioxiderdquo Journalof Hazardous Materials vol 248-249 pp 478ndash486 2013

[41] T Fifis A Gamvrellis B Crimeen-Irwin et al ldquoSize-dependentimmunogenicity therapeutic and protective properties ofnano-vaccines against tumorsrdquo Journal of Immunology vol 173no 5 pp 3148ndash3154 2004

[42] M Zhu X Tian X Song et al ldquoNanoparticle-inducedexosomes target antigen-presenting cells to initiate Th1-typeimmune activationrdquo Small vol 8 no 18 pp 2841ndash2848 2012

[43] M Zhu Y Li J ShiW Feng G Nie and Y Zhao ldquoExosomes asextrapulmonary signaling conveyors for nanoparticle-inducedsystemic immune activationrdquo Small vol 8 no 3 pp 404ndash4122012

[44] C C Shen H H Liang C C Wang M H Liao and T R JanldquoIron oxide nanoparticles suppressed T helper 1 cell-mediatedimmunity in a murine model of delayed-type hypersensitivityrdquoInternational Journal of Nanomedicine vol 7 pp 2729ndash27372012

[45] M Ban I Langonne N Huguet Y Guichard and M GoutetldquoIron oxide particles modulate the ovalbumin-induced Th2immune response inmicerdquo Toxicology Letters vol 216 no 1 pp31ndash39 2013

[46] C J Wingard D M Walters B L Cathey et al ldquoMastcells contribute to altered vascular reactivity and ischemia-reperfusion injury following cerium oxide nanoparticle instil-lationrdquo Nanotoxicology vol 5 no 4 pp 531ndash545 2011

[47] J Y Ma H Zhao R R Mercer et al ldquoCerium oxidenanoparticle-induced pulmonary inflammation and alveolarmacrophage functional change in ratsrdquo Nanotoxicology vol 5no 3 pp 312ndash325 2011

[48] W-S Cho R Duffn C A Poland et al ldquoMetal oxide nanopar-ticles induce unique infammatory footprints in the lungimportant implications for nanoparticle testingrdquoEnvironmentalHealth Perspectives vol 118 no 12 pp 1699ndash1706 2010

[49] A Srinivas P J Rao G Selvam P B Murthy and P N ReddyldquoAcute inhalation toxicity of cerium oxide nanoparticles in ratsrdquoToxicology Letters vol 205 no 2 pp 105ndash115 2011


[50] F Gagne J Auclair P Turcotte et al ldquoEcotoxicity of CdTequantum dots to freshwater mussels impacts on immunesystem oxidative stress and genotoxicityrdquo Aquatic Toxicologyvol 86 no 3 pp 333ndash340 2008

[51] F Gagne M Fortier L Yu et al ldquoImmunocompetence andalterations in hepatic gene expression in rainbow trout exposedto CdSCdTe quantum dotsrdquo Journal of EnvironmentalMonitor-ing vol 12 no 8 pp 1556ndash1565 2010

[52] T Morishige Y Yoshioka H Inakura et al ldquoSuppression ofnanosilica particle-induced inflammation by surface modifica-tion of the particlesrdquo Archives of Toxicology vol 86 no 8 pp1297ndash1307 2012

[53] Q Chen Y Xue and J Sun ldquoKupffer cell-mediated hepaticinjury induced by silica nanoparticles in vitro and in vivordquoInternational Journal of Nanomedicine vol 8 pp 1129ndash11402013

[54] C L Hardy J S LeMasurier G T Belz et al ldquoInert 50-nmpolystyrene nanoparticles thatmodify pulmonary dendritic cellfunction and inhibit allergic airway inflammationrdquo Journal ofImmunology vol 188 no 3 pp 1431ndash1441 2012

[55] D R Getts A J Martin D P McCarthy et al ldquoMicroparti-cles bearing encephalitogenic peptides induce T-cell toleranceand ameliorate experimental autoimmune encephalomyelitisrdquoNature Biotechnology vol 30 no 12 pp 1217ndash1224 2012

[56] P M Daftarian G W Stone L Kovalski et al ldquoA targeted andadjuvanted nanocarrier lowers the effective dose of liposomalamphotericin B and enhances adaptive immunity in murinecutaneous leishmaniasisrdquo Journal of InfectiousDiseases vol 208no 11 pp 1914ndash1922 2013

[57] N Saljoughian F Zahedifard D Doroud et al ldquoCationic solid-lipid nanoparticles are as efficient as electroporation in DNAvaccination against visceral leishmaniasis in micerdquo ParasiteImmunology vol 35 no 12 pp 397ndash408 2013

[58] D R Weilhammer C D Blanchette N O Fischer et al ldquoTheuse of nanolipoprotein particles to enhance the immunostim-ulatory properties of innate immune agonists against lethalinfluenza challengerdquo Biomaterials vol 34 no 38 pp 10305ndash10318 2013

[59] A Chanan-Khan J Szebeni S Savay et al ldquoComplementactivation following first exposure to pegylated liposomal dox-orubicin (Doxil) possible role in hypersensitivity reactionsrdquoAnnals of Oncology vol 14 no 9 pp 1430ndash1437 2003

[60] S Mahajan V Koul V Choudhary et al ldquoPreparation andin vitro evaluation of folate-receptor-targeted SPIONndashpolymermicelle hybrids for MRI contrast enhancement in cancerimagingrdquoNanotechnology vol 24 no 1 Article ID 015603 2013

[61] A Eldar-Boock D Polyak A Scomparin and R Satchi-Fainaro ldquoNano-sized polymers and liposomes designed todeliver combination therapy for cancerrdquo Current Opinion inBiotechnology vol 24 no 4 pp 682ndash689 2013

[62] J K Jaiswal and S M Simon ldquoBelling the catmdashtagging live cellswith quantum dotsrdquo Clinical Chemistry vol 59 no 6 pp 995ndash996 2013

[63] C H Liu S Huang J Cui et al ldquoMR contrast probes thattrace gene transcripts for cerebral ischemia in live animalsrdquoTheFASEB Journal vol 21 no 11 pp 3004ndash3015 2007

[64] K Kostarelos A Bianco and M Prato ldquoPromises facts andchallenges for carbon nanotubes in imaging and therapeuticsrdquoNature Nanotechnology vol 4 no 10 pp 627ndash633 2009

[65] J E Podesta K T Al-Jamal M A Herrero et al ldquoAntitumoractivity and prolonged survival by carbon-nanotube-mediated

therapeutic siRNA silencing in a human lung xenograftmodelrdquoSmall vol 5 no 10 pp 1176ndash1185 2009

[66] H Zhang G Gruner and Y Zhao ldquoRecent advancements ofgraphene in biomedicinerdquo Journal ofMaterials Chemistry B vol1 no 20 p 2542 2013

[67] O Akhavan and E Ghaderi ldquoEscherichia coli bacteria reducegraphene oxide to bactericidal graphene in a self-limitingmannerrdquo Carbon vol 50 no 5 pp 1853ndash1860 2012

[68] C Loo A Lin L Hirsch et al ldquoNanoshell-enabled photonics-based imaging and therapy of cancerrdquo Technology in CancerResearch amp Treatment vol 3 no 1 pp 33ndash40 2004

[69] Y Cheng A C Samia J DMeyers I Panagopoulos B Fei andC Burda ldquoHighly efficient drug delivery with gold nanoparticlevectors for in vivo photodynamic therapy of cancerrdquo Journal ofthe American Chemical Society vol 130 no 32 pp 10643ndash106472008

[70] Q H Tran V Q Nguyen and A-T Le ldquoSilver nanoparticlessynthesis properties toxicology applications and perspectivesrdquoAdvances in Natural Sciences Nanoscience and Nanotechnologyvol 4 no 3 Article ID 033001 2013

[71] J C Kraft J P Freeling Z Wang and R J Y Ho ldquoEmergingresearch and clinical development trends of liposome and lipidnanoparticle drug delivery systemsrdquo Journal of PharmaceuticalSciences vol 103 no 1 pp 29ndash52 2013

[72] J M Silva M Videira R Gaspar V Preat and H F FlorindoldquoImmune system targeting by biodegradable nanoparticles forcancer vaccinesrdquo Journal of Controlled Release vol 168 no 2pp 179ndash199 2013

[73] S M Hirst A S Karakoti R D Tyler N Sriranganathan SSeal and C M Reilly ldquoAnti-inflammatory properties of ceriumoxide nanoparticlesrdquo Small vol 5 no 24 pp 2848ndash2856 2009

[74] J-H Park L Gu G von Maltzahn E Ruoslahti S N Bhatiaand M J Sailor ldquoBiodegradable luminescent porous siliconnanoparticles for in vivo applicationsrdquo Nature Materials vol 8no 4 pp 331ndash336 2009

[75] J Salonen L Laitinen A M Kaukonen et al ldquoMesoporoussiliconmicroparticles for oral drug delivery loading and releaseof five model drugsrdquo Journal of Controlled Release vol 108 no2-3 pp 362ndash374 2005

[76] P M Heegaard U Boas and N S Sorensen ldquoDendrimers forvaccine and immunostimulatory uses a reviewrdquo BioconjugateChemistry vol 21 no 3 pp 405ndash418 2010

[77] Y Yang T Neef C Mittelholzer et al ldquoThe biodistribution ofself-assembling protein nanoparticles shows they are promisingvaccine platformsrdquo Journal of Nanobiotechnology vol 11 no 1p 36 2013

[78] M J Hawkins P Soon-Shiong andN Desai ldquoProtein nanopar-ticles as drug carriers in clinical medicinerdquo Advanced DrugDelivery Reviews vol 60 no 8 pp 876ndash885 2008

[79] S C Chueh M K Lai M S Lee L Y Chiang T I Ho andS C Chen ldquoDecrease of free radical level in organ perfusate bya novel water-soluble carbon-sixty hexa(sulfobutyl)fullerenesrdquoTransplantation Proceedings vol 31 no 5 pp 1976ndash1977 1999

[80] G E Magoulas T Garnelis C M Athanassopoulos et al ldquoSyn-thesis and antioxidativeanti-inflammatory activity of novelfullerene-polyamine conjugatesrdquo Tetrahedron vol 68 no 35pp 7041ndash7049 2012

[81] Y W Chen K C Hwang C Yen and Y Lai ldquoFullerenederivatives protect against oxidative stress in RAW 2647 cellsand ischemia-reperfused lungsrdquoThe American Journal of Phys-iology Regulatory Integrative and Comparative Physiology vol287 no 1 pp R21ndashR26 2004


[82] M F Rahman J Wang T A Patterson et al ldquoExpressionof genes related to oxidative stress in the mouse brain afterexposure to silver-25 nanoparticlesrdquo Toxicology Letters vol 187no 1 pp 15ndash21 2009

[83] M E Samberg S J Oldenburg and N A Monteiro-RiviereldquoEvaluation of silver nanoparticle toxicity in skin in vivo andkeratinocytes in vitrordquo Environmental Health Perspectives vol118 no 3 pp 407ndash413 2010

[84] K Muller J N Skepper M Posfai et al ldquoEffect of ultrasmallsuperparamagnetic iron oxide nanoparticles (Ferumoxtran-10)on human monocyte-macrophages in vitrordquo Biomaterials vol28 no 9 pp 1629ndash1642 2007

[85] A Gojova B Guo R S Kota J C Rutledge I M Kennedyand A I Barakat ldquoInduction of inflammation in vascularendothelial cells by metal oxide nanoparticles effect of particlecompositionrdquo Environmental Health Perspectives vol 115 no 3pp 403ndash409 2007

[86] S Naqvi M Samim M Z Abdin et al ldquoConcentration-dependent toxicity of iron oxide nanoparticles mediatedby increased oxidative stressrdquo International Journal ofNanomedicine vol 5 no 1 pp 983ndash989 2010

[87] F Blank P Gerber B Rothen-Rutishauser et al ldquoBiomedicalnanoparticles modulate specific CD4(+) T cell stimulation byinhibition of antigen processing in dendritic cellsrdquo Nanotoxi-cology vol 5 no 4 pp 606ndash621 2011

[88] M Ban I Langonne N Huguet and M Goutet ldquoEffectof submicron and nano-iron oxide particles on pulmonaryimmunity in micerdquo Toxicology Letters vol 210 no 3 pp 267ndash275 2012

[89] B C Schanen S Das C M Reilly et al ldquoImmunomodulationandThelper TH

1TH2response polarization byCeO

2andTiO

2

nanoparticlesrdquo PLoS ONE vol 8 no 5 Article ID e62816 2013[90] F Pagliari CMandoli G Forte et al ldquoCeriumoxide nanoparti-

cles protect cardiac progenitor cells from oxidative stressrdquo ACSNano vol 6 no 5 pp 3767ndash3775 2012

[91] C FalugiM G AluigiM C Chiantore et al ldquoToxicity ofmetaloxide nanoparticles in immune cells of the sea urchinrdquoMarineEnvironmental Research vol 76 pp 114ndash121 2012

[92] A R Clapp I L Medintz J M Mauro B R Fisher M GBawendi and H Mattoussi ldquoFluorescence resonance energytransfer between quantum dot donors and dye-labeled proteinacceptorsrdquo Journal of the American Chemical Society vol 126no 1 pp 301ndash310 2004

[93] A C Samia X Chen and C Burda ldquoSemiconductor quantumdots for photodynamic therapyrdquo Journal of the American Chem-ical Society vol 125 no 51 pp 15736ndash15737 2003

[94] J Lovric S J Cho F M Winnik and D Maysinger ldquoUnmod-ified cadmium telluride quantum dots induce reactive oxygenspecies formation leading tomultiple organelle damage and celldeathrdquo Chemistry amp Biology vol 12 no 11 pp 1227ndash1234 2005

[95] K C Nguyen V L Seligy and A F Tayabali ldquoCadmiumtelluride quantum dot nanoparticle cytotoxicity and effectson model immune responses to Pseudomonas aeruginosardquoNanotoxicology vol 7 no 2 pp 202ndash211 2013

[96] A Hoshino S Hanada N Manabe T Nakayama andK Yamamoto ldquoImmune response induced by fluorescentnanocrystal quantum dots in vitro and in vivordquo IEEE Transac-tions on Nanobioscience vol 8 no 1 pp 51ndash57 2009

[97] A Bruneau M Fortier F Gagne et al ldquoSize distribution effectsof cadmium tellurium quantum dots (CdSCdTe) immunotox-icity on aquatic organismsrdquo Environmental Science Processes ampImpacts vol 15 no 3 pp 596ndash607 2013

[98] R A Roberts T Shen I C Allen W Hasan J M DeS-imone and J P Y Ting ldquoAnalysis of the murine immuneresponse to pulmonary delivery of precisely fabricated nano-and microscale particlesrdquo PLoS ONE vol 8 no 4 Article IDe62115 2013

[99] S Clichici A R Biris C Catoi A Filip and F Tabaran ldquoShort-term splenic impact of single-strandDNA functionalizedmulti-walled carbon nanotubes intraperitoneally injected in ratsrdquoJournal of Applied Toxicology vol 34 no 4 pp 332ndash344 2013

[100] U C Nygaard J S Hansen M Samuelsen T Alberg CD Marioara and M Loslashvik ldquoSingle-walled and multi-walledcarbon nanotubes promote allergic immune responses inmicerdquoToxicological Sciences vol 109 no 1 pp 113ndash123 2009

[101] G Laverny A Casset A Purohit et al ldquoImmunomodulatoryproperties of multi-walled carbon nanotubes in peripheralblood mononuclear cells from healthy subjects and allergicpatientsrdquo Toxicology Letters vol 217 no 2 pp 91ndash101 2013

[102] X Zhi H Fang C Bao et al ldquoThe immunotoxicity of grapheneoxides and the effect of PVP-coatingrdquo Biomaterials vol 34 no21 pp 5254ndash5261 2013

[103] A V Tkach N Yanamala S Stanley et al ldquoGraphene oxidebut not fullerenes targets immunoproteasomes and suppressesantigen presentation by dendritic cellsrdquo Small vol 9 no 9-10pp 1686ndash1690 2013

[104] G-Y Chen H-J Yang C-H Lu et al ldquoSimultaneous inductionof autophagy and toll-like receptor signaling pathways bygraphene oxiderdquo Biomaterials vol 33 no 27 pp 6559ndash65692012

[105] H Yue W Wei Z Yue et al ldquoThe role of the lateral dimensionof graphene oxide in the regulation of cellular responsesrdquoBiomaterials vol 33 no 16 pp 4013ndash4021 2012

[106] H Bunz S Plankenhorn and R Klein ldquoEffect of buckminster-fullerenes on cells of the innate and adaptive immune systeman in vitro study with human peripheral blood mononuclearcellsrdquo International Journal of Nanomedicine vol 7 pp 4571ndash4580 2012

[107] S Fallarini T Paoletti C O Battaglini et al ldquoFactors affect-ing T cell responses induced by fully synthetic glyco-gold-nanoparticlesrdquo Nanoscale vol 5 no 1 pp 390ndash400 2013

[108] T Pfaller V Puntes E Casals A Duschl and G J OostinghldquoIn vitro investigation of immunomodulatory effects caused byengineered inorganic nanoparticles the impact of experimentaldesign and cell choicerdquo Nanotoxicology vol 3 no 1 pp 46ndash592009

[109] E-J Yang and I-H Choi ldquoImmunostimulatory effects of silicananoparticles in human monocytesrdquo Immune Network vol 13no 3 pp 94ndash101 2013

[110] P J LouW Cheng Y Chung C Cheng L Chiu and T YoungldquoPMMA particle-mediated DNA vaccine for cervical cancerrdquoJournal of Biomedical Materials Research A vol 88 no 4 pp849ndash857 2009

[111] J Kreuter and E Liehl ldquoProtection induced by inactivatedinfluenza virus vaccines with polymethylmethacrylate adju-vantsrdquo Medical Microbiology and Immunology vol 165 no 2pp 111ndash117 1978

[112] A K Shakya and K S Nandakumar ldquoApplications of polymericadjuvants in studying autoimmune responses and vaccinationagainst infectious diseasesrdquo Journal of the Royal Society Inter-face vol 10 no 79 Article ID 20120536 2012

[113] B Sayin S Somavarapu X W Li D Sesardic S Seneland O H Alpar ldquoTMC-MCC (N-trimethyl chitosan-mono-N-carboxymethyl chitosan) nanocomplexes for mucosal delivery


of vaccinesrdquo The European Journal of Pharmaceutical Sciencesvol 38 no 4 pp 362ndash369 2009

[114] L K Petersen A E Ramer-Tait S R Broderick et al ldquoActi-vation of innate immune responses in a pathogen-mimickingmanner by amphiphilic polyanhydride nanoparticle adjuvantsrdquoBiomaterials vol 32 no 28 pp 6815ndash6822 2011

[115] A I Camacho R da Costa Martins I Tamayo et alldquoPoly(methyl vinyl ether-co-maleic anhydride) nanoparticles asinnate immune system activatorsrdquo Vaccine vol 29 no 41 pp7130ndash7135 2011

[116] S U Frick N Bacher G Baier et al ldquoFunctionalizedpolystyrene nanoparticles trigger human dendritic cell matu-ration resulting in enhanced CD4+T cell activationrdquo Macro-molecular Bioscience vol 12 no 12 pp 1637ndash1647 2012

[117] E V Cordoba M Pion B Rasines et al ldquoGlycodendrimersas new tools in the search for effective anti-HIV DC-basedimmunotherapiesrdquoNanomedicine Nanotechnology Biology andMedicine vol 9 no 7 pp 972ndash984 2013

[118] M E McCoy H E Golden T A Doll et al ldquoMechanismsof protective immune responses induced by the Plasmodiumfalciparum circumsporozoite protein-based self-assemblingprotein nanoparticle vaccinerdquo Malaria Journal vol 12 no 1 p136 2013

[119] S Walker Biophysical characterization of optimized self-assembling protein nanoparticles as a malaria vaccine [HonorsScholar Thesis] University of Connecticut Storrs Conn USA2013

[120] N M Molino A K L Anderson E L Nelson and W Szu-Wen ldquoBiomimetic protein nanoparticles facilitate enhanceddendritic cell activation and cross-presentationrdquoACSNano vol7 no 11 pp 9743ndash9752 2013

[121] Q Guo D Dasgupta T A Doll P Burkhard and D E LanarldquoExpression purification and refolding of a self-assemblingprotein nanoparticle (SAPN) malaria vaccinerdquo Methods vol160 no 3 pp 242ndash247 2013

[122] H Akita S Ishii N Miura et al ldquoA DNA microarray-basedanalysis of immune-stimulatory and transcriptional responsesof dendritic cells to KALA-modified nanoparticlesrdquo Biomateri-als vol 34 no 35 pp 8979ndash8990 2013

[123] K Sellins L Fradkin D Liggitt and S Dow ldquoType I interferonspotently suppress gene expression following gene delivery usingliposome-DNAcomplexesrdquoMolecularTherapy vol 12 no 3 pp451ndash459 2005

[124] H Zhou Q Mu N Gao et al ldquoA nano-combinatorial librarystrategy for the discovery of nanotubes with reduced protein-binding cytotoxicity and immune responserdquoNano Letters vol8 no 3 pp 859ndash865 2008

[125] N Gao Q Zhang Q Mu et al ldquoSteering carbon nanotubes toscavenger receptor recognition by nanotube surface chemistrymodification partially alleviatesNF120581B activation and reduces itsimmunotoxicityrdquo ACS Nano vol 5 no 6 pp 4581ndash4591 2011

[126] Y Jiang H Zhang Y Wang et al ldquoModulation of apoptoticpathways of macrophages by surface-functionalized multi-walled carbon nanotubesrdquo PLoS ONE vol 8 no 6 Article IDe65756 2013

[127] M A Shahbazi M Hamidi E M Makila et al ldquoThe mech-anisms of surface chemistry effects of mesoporous siliconnanoparticles on immunotoxicity and biocompatibilityrdquo Bio-materials vol 34 no 31 pp 7776ndash7789 2013

[128] P L Mottram D Leong B Crimeen-Irwin et al ldquoType 1 and2 immunity following vaccination is influenced by nanoparticle

size formulation of a model vaccine for respiratory syncytialvirusrdquoMolecular Pharmaceutics vol 4 no 1 pp 73ndash84 2007

[129] D Walczyk F B Bombelli M P Monopoli I Lynch and K ADawson ldquoWhat the cell ldquoseesrdquo in bionanosciencerdquo Journal of theAmerican Chemical Society vol 132 no 16 pp 5761ndash5768 2010

[130] F Marano S Hussain F Rodrigues-Lima A Baeza-Squibanand S Boland ldquoNanoparticles molecular targets and cellsignallingrdquo Archives of Toxicology vol 85 no 7 pp 733ndash7412011

[131] T Cedervall I Lynch S Lindman et al ldquoUnderstandingthe nanoparticle-protein corona using methods to quntifyexchange rates and affinities of proteins for nanoparticlesrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 104 no 7 pp 2050ndash2055 2007

[132] Z J Deng M Liang M Monteiro and R F Minchin ldquoPlasmaprotein binding of positively and negatively charged polymer-coated gold nanoparticles elicits different biological responsesrdquoNanotoxicology vol 7 no 3 pp 314ndash322 2012

[133] M Horie K Nishio K Fujita et al ldquoProtein adsorption ofultrafine metal oxide and its influence on cytotoxicity towardcultured cellsrdquo Chemical Research in Toxicology vol 22 no 3pp 543ndash553 2009

[134] I Lynch andK A Dawson ldquoProtein-nanoparticle interactionsrdquoNano Today vol 3 no 1-2 pp 40ndash47 2008

[135] Z J Deng G Mortimer T Schiller A Musumeci D MartinandR FMinchin ldquoDifferential plasma protein binding tometaloxide nanoparticlesrdquoNanotechnology vol 20 no 45 Article ID455101 2009

[136] S R Saptarshi A Duschl and A L Lopata ldquoInteraction ofnanoparticles with proteins relation to bio-reactivity of thenanoparticlerdquo Journal of Nanobiotechnology vol 11 no 1 pp 1ndash12 2013

[137] M Lundqvist J Stigler G Elia I Lynch T Cedervall and K ADawson ldquoNanoparticle size and surface properties determinethe protein corona with possible implications for biologicalimpactsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 38 pp 14265ndash14270 2008

[138] C Sacchetti K Motamedchaboki A Magrini et al ldquoSur-face polyethylene glycol conformation influences the proteincorona of polyethylene glycol-modified single-walled carbonnanotubes potential implications on biological performancerdquoACS Nano vol 7 no 3 pp 1974ndash1989 2013

[139] Z J Deng M Liang M Monteiro I Toth and R F MinchinldquoNanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammationrdquo Nature Nanotechnol-ogy vol 6 no 1 pp 39ndash44 2011

[140] D Pantarotto J Briand M Prato and A Bianco ldquoTranslo-cation of bioactive peptides across cell membranes by carbonnanotubesrdquo Chemical Communications vol 10 no 1 pp 16ndash172004

[141] D Guo L Zhu Z Huang et al ldquoAnti-leukemia activity of PVP-coated silver nanoparticles via generation of reactive oxygenspecies and release of silver ionsrdquo Biomaterials vol 34 no 32pp 7884ndash7894 2013

[142] I L C Chapple ldquoReactive oxygen species and antioxidants ininflammatory diseasesrdquo Journal of Clinical Periodontology vol24 no 5 pp 287ndash296 1997

[143] H Wiseman and B Halliwell ldquoDamage to DNA by reactiveoxygen and nitrogen species role in inflammatory disease andprogression to cancerrdquo Biochemical Journal vol 313 pp 17ndash291996


[144] G Qu S Liu S Zhang et al ldquoGraphene oxide induces toll-likereceptor 4 (TLR4)-dependent necrosis in macrophagesrdquo ACSNano vol 7 no 7 pp 5732ndash5745 2013

[145] K Lucas and M Maes ldquoRole of the toll like receptor (TLR)radical cycle in chronic inflammation possible treatmentstargeting the TLR4 pathwayrdquo Molecular Neurobiology vol 48no 1 pp 190ndash204 2013

[146] C-C Ho Y-H Luo T-H Chuang C-S Yang Y-C Ling andP Lin ldquoQuantum dots induced monocyte chemotactic protein-1 expression via MyD88-dependent Toll-like receptor signalingpathways in macrophagesrdquo Toxicology vol 308 no 7 pp 1ndash92013

[147] M Pasparakis ldquoRegulation of tissue homeostasis by NF-Bsignalling implications for inflammatory diseasesrdquo NatureReviews Immunology vol 9 no 11 pp 778ndash788 2009

[148] P P Tak and G S Firestein ldquoNF-120581B a key role in inflammatorydiseasesrdquo Journal of Clinical Investigation vol 107 no 1 pp 7ndash112001

[149] P A Baeuerle and T Henkel ldquoFunction and activation of NF-120581B in the immune systemrdquo Annual Review of Immunology vol12 pp 141ndash179 1994

[150] S Z Wang F M Ma and J D Zhao ldquoExpressions of nuclearfactor-kappa B p50 and p65 and their significance in the up-regulation of intercellular cell adhesion molecule-1 mRNA inthe nasalmucosa of allergic rhinitis patientsrdquoEuropeanArchivesof Oto-Rhino-Laryngology vol 270 no 4 pp 1329ndash1334 2012

[151] J K Patel R L Clifford KDeacon andA J Knox ldquoCiclesonideinhibits TNF120572- and IL-1120573-induced monocyte chemotacticprotein-1 (MCP-1CCL2) secretion from human airway smoothmuscle cellsrdquoTheAmerican Journal of Physiology Lung Cellularand Molecular Physiology vol 302 no 8 pp L785ndashL792 2012

[152] M Sharma R L Salisbury E IMaurer SMHussain andC EW Sulentic ldquoGold nanoparticles induce transcriptional activityof NF-120581B in a B-lymphocyte cell linerdquo Nanoscale vol 5 no 9pp 3747ndash3756 2013

[153] K-I Inoue R Yanagisawa E Koike M Nishikawa andH Takano ldquoRepeated pulmonary exposure to single-walledcarbon nanotubes exacerbates allergic inflammation of theairway possible role of oxidative stressrdquo Free Radical Biologyand Medicine vol 48 no 7 pp 924ndash934 2010

[154] M de Nicola D M Gattia E Traversa and L GhibellildquoMaturation and demise of human primary monocytes bycarbon nanotubesrdquo Journal of Nanoparticle Research vol 15article 1711 2013

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of



CeramicsJournal of


CompositesJournal of

NanoparticlesJournal of



International Journal of

Biomaterials


NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research



MetallurgyJournal of


BioMed Research International

MaterialsJournal of


Nano

materials


Journal ofNanomaterials


results in a decreased immune function and thereby leads topathogen which cannot be effectively cleared and infection ortumorwill occur [12] Immunostimulation could enhance theability to resist pathogen but it may result in a strong adverseresponse such as autoimmune disease if it was hypersensitive

When nanomedicines are applied in vivo they act asforeignmaterials and induce the immune response immuno-suppression or immunostimulation [13] However thesemodulations of immune system caused by NPs are unde-sirable in most cases when nanomedicine is applied suchas imaging Furthermore these immune modulations byNPs could be adverse in other conditions Some nanobasedanticancer therapeutic agents show antitumor properties invitro but tumor-promoting effect in vivo [14] This oppositeeffect may be due to the disturbed anticancer immunesystem [14] However some immunomodulation propertiesare good for disease prevention and treatment such asvaccine adjuvant and antiallergy therapeutic agents [15 16]Therefore NPs play as a Janusrsquo double-face in nanomedicineapplications (Figure 1) Immunomodulating potential of NPsshould be considered seriously because it could bring unex-pected side effects in the clinical treatment Understandingof nano-immuno-interactions is critical for the safe appli-cation of engineered NPs in medicine and safe design ofnanomedicine

In this review we focus on the immunomodulatingeffects of NPs used in nanomedicine on immune system(Table 1) Effects of physicochemical properties of NPs onimmune interactions and the underlying mechanisms arealso reviewed

2 NPs Candidates Used in Nanomedicine

Nanotechnology has a great potential in medicine applica-tions such as medical diagnostics [60] and therapy [61] Asan inorganic fluorophore quantum dots (QDs) have pho-tostability which makes them ideal candidates for imagingtools in vivo [62] Recent study showed a technique to tracklymph flow in real time using quantum dots optical imagingin mice [22] In addition superparamagnetic iron oxideNPs (SPION) were also applied to trace neurodegenerativediseases by magnetic resonance imaging (MRI) [63] Somecarbon-based NPs are also applied in clinical use Carbonnanotubes (CNTs) have unique physical properties such aselectrical thermal and spectroscopic properties whichmakethem an advantage in detection and therapy of diseases [64]It was reported that CNTs could prolong survival of tumor-bearing animals [65] Graphene has good biocompatibilitybiofunctionalization and its unique mechanical electronicand optical properties for imaging and cancer phototherapy[66] And it was demonstrated that graphene oxide (GO)have antibacterial properties [67] making them candidatesas antibacterial agent Besides graphene derivatives are alsogood candidates for drug delivery as they can bind witharomatic drugs through120587-120587 stack andor van derWaals inter-actions [66] Gold NPs (GNPs) are also potential materials incancer therapies and imaging due to their biocompatibilityplasmon resonances and diverse functionalizations [68] It

Anti-inflammatory

Antiallergic

Vaccine adjuvantAnticancer

Antibacterial

Incapacitate bodyrsquos immunesystem to unwanted mass

Inflammation

Immunosuppression

Immunostimulation

Nanoparticles

Figure 1 The immunomodulation of NPs presents a Janusrsquo double-face in nanomedicine applications On one hand the effects to theimmune systemmay benefit treatment of disease through enhancingimmune response On the other hand the immunomodulation ofNPs may bring harm

is promising to apply GNPs to targeted therapy of cancer[69] and overcome drug resistance [6] Silver NPs (AgNPs)are important metal nanomaterial They have antibacterialantifungal and antiviral effects [70] Lipid NPs and liposomehave been widely applied for drug delivery because of theirimproved drug potency and low off-target effects [71] OtherNPs such as polymer CeO

2 silica NPs dendrimer and

protein NPs are also used in nanomedicine [72ndash78]As foreign materials NPs could be recognized by the

immune system and induce immunosuppression or immun-ostimulation when used as nanomedicine How to utilizeor control these immunomodulation effects is largely basedon NPsrsquo different applications NPs with immunosuppressioneffects might be used as anti-inflammatory or antiautoim-mune disease therapeutic agents On the contrast NPs whichactivate immune systemmight be used as vaccines or vaccineadjuvants An advanced nanomedicine in drug delivery orimaging should not induce undesired immune-activation orimmunosuppression effectThe detailed immunomodulationeffects of these NPs in nanomedicine applications are dis-cussed below

3 Immunomodulation by Different NPs

31 Immunosuppression

311 Carbon Nanotubes After inhalation exposure CNTsinduced systemic immunosuppression in mice includingproduction of prostaglandin and IL-10 [17 18] and T celldysfunction [18 19 23] For example inhalation of CNTs (031 or 5mgm3 6 hday 14 days) hardly induced injury in lungsbut resulted in nonmonotonic systemic immunosuppression


Table1Im

mun

omod

ulationof

vario

usnano

particlesinnano

medicinea

pplications

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Carbon

nano

tube

MWCN

TL5ndash15120583m

Inhalatio

n5m

gm

3

6hday

14days

Immun

osup

pressio

nTG


MaleC

57BL

6[1718]

D10ndash

20nm

SWCN

TL1ndash3120583

mPh

aryn

gealaspiratio

n40

80120120583gmou

seInflammation

immun

osup

pressio

nTN


CP1uarr

FemaleB

ALB

candC5

7BL6

[19]

D1ndash4

nm

MWCN

TLseveral120583

mOroph

aryn

gealaspiratio

n1

2and4m

gkg

Inflammation

IL-33uarrC

CL3uarrC

CL11uarr

C57B

L6

[2021]

D125ndash25

nm

MWCN

TLseveral120583

mOroph

aryn

gealaspiratio

n4m

gkg

Inflammation


C57B

L6

[22]

D125ndash25

nm

MWCN

TL15plusmn5120583m

Intravenou

sly1m

gkg

Inflammation

IL-4uarrIL-33uarr

C57B

L6

[23]

D25plusmn5nm

MWCN

TL50120583m

Subcutaneous

00503and

05m

gtimes2mou

seAc

uteinfl

ammation


IFN-120574uarr

BALB

c[24]

D20ndash

30nm

MWCN

TL03ndash50120583m

Inhalatio

n100m

gm

3times6h

Hypersensitivity

PDGF-AAuarrT

GF-120573uarr

Allergicasthmam

ice

(C57BL

6)

[25]

D30ndash

50nm

SWCN

TL3ndash30120583m


6mou

seHypersensitivity


-120574uarr



(maleICR

)[26]

D67n

mGraph

ene

Graph

ene

4plusmn1120583m

2area

Intravenou

sly1m

gkg

Activ

ateTh

2im

mun

erespon


C57B

L6

[23]

2plusmn1nm

thick

Fullerene

C60

NA

Intravenou

sly50

ngm

ouse

Immun

osup

pressio

nSerum

histam

inedarrLyndarr

SykdarrR

OSdarr

MC-

depend

entm

odelof

anaphylaxis(C5

7BL6)

[16]

C60

NA

Intra-artic

ular

treatment

100120583Mw

eektimes8week

Immun

osup

pressio

nTN


Ratm

odelof

arthritis(fe

male

Sprague-Daw

leyrats)

[27]

C60

NA

Instillatio

n2m

gkg

Inflammation

IL-1uarrT


IFN-120574uarr

MaleICR

[2829]

Carboxyfullerene

NA

Periton

eum

andairp

ouch

40mgkg

Activ

ateimmun

esyste

mNA

C57B

L6

[30]

HydroxylatedC6

0NA


2120583gg

Immun

osup

pressio

nIL-11uarrelasta

se2genedarr

Fatheadminno

w[31]

C60

NA

Intraperito

nealinjection

05m


days

Immun

osup

pressio

nIFN-120574uarr

Tumor-bearin

gmice

(C57BL

6)

[14]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Goldnano

particles

PfMSP-1

19PvM

SP-1

19coated

GNPs

form

ulated

with

alum

17nm

Subcutaneously25

120583gmou

seIm

mun

ogenic

Antibod

ytiteruarr

BALB

c[15]

PfMSP-1

19PvM

SP-1

19coated

GNPs

17nm

Subcutaneously

25120583gmou

sePo

orim

mun

ogenic

NA

BALB

c[15]

Short-c

hain

PEG

mixed-m

onolayer

protectedgold

cluste

rslt5n


40120583Mtimes200120583

LIm

mun

ogenic

Antibod

ytiteruarr

BALB

cAnN

Hsd

[3233]

PEGcoated

GNP

13nm

Intravenou

sly0017085

or426

mgkg

Acuteinfl

ammation

MCP

-1C

CL-2uarr

MIP-1120572C

CL-3uarrM

IP-1120573uarr

RANTE

SCC



TNF-120572uarr

BALB

c[34]

GNPfunctio

nalized

with


cid

(MES

)orN

NN-

trim

ethylammon

iumethanethiol

(TMAT

)

15nm

Mediaexpo

sure

0016ndash

250p

pm

Activ

ateimmun

erespon

seInflammatory

respon

se


Zebrafish

embryos

[35]


40nm

Oroph

aryn

gealaspiratio

n08m

gkg

Hypersensitivity

MMP-9uarrM

IP-2uarrT

NF-120572darr

IL-6darr


LBc)

[36]

GNP

21nm

Intraperito

neallyinjection

785120583

gg

Antiflam

matory

TNF-120572mRN

AdarrIL-6mRN

Adarr

MaleC

57BL

6[37]


5nm

100n

molAu

kg

Antiflam

matory

IL-1120573darr

IL-1120573mod

elmice(male

C57B

L6)

[38]

Silver

Nanop

articles

AgN

P2218plusmn172nm

Inhalatio


3times

6hdaytimes5daysw

eektimes2

weeks

Immun

osup

pressio

nMalt1genedarrSem

a7ag

enedarr

C57B

L6

[39]

AgN

P5225plusmn2364nm


n35

or175m

gkg

once

every2

days

for5

weeks

Enhanceimmun

efunctio

nIL-1uarrIL-6uarrT

NF-120572uarrG

SHdarr

T-SO

DdarrM

DAuarrN

Ouarr

Wistar

rats

[40]

Agconjugated

tocore

nano

beads40

ndash50n

mIntradermally

Immun

ogenic


yuarrH-2Kb

C57B

L6

[41]

Magnetic

Nanop

articles

Iron

Oxide

NP

43nm


n(4

or20120583gtimes3)

Activ

ateimmun

erespon


OVA

-sensitized

mice

(BALB

c)

[4243]

Iron

Oxide

NP

587nm

Intravenou

slyle10mg

ironkg

Immun

osup

pressio


NF-120572darr

DTH

mice(maleB

ALB

c)

[44]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Iron

Oxide

NP

35plusmn14nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

OVA

-sensitized

mice

(BALB

c)

[45]

Intratracheally

4times100120583gmou

seHypersensitivity

IgEuarr

IL-4uarr

147plusmn48nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

Intratracheally

4times100120583gmou

seNosig

nificanteffect

NA

Nanoceria

Nanoceria

D8

nmOroph

aryn

gealinstillatio

nof

1030or

100120583

gmou

seInflammation


opon

tinuarr

C57B

L6

[46]

A44m

2 g

Nanoceria

20nm

Sing

leintratracheal


mgkg

Inflammation

NOdarrIL-12uarr

Specificp

atho

gen-fre

emale

Sprague-Daw

ley(H

la

SD-C

VF)

rats

[47]

Nanoceria

D20ndash

30nm


nat

50and150m

2 mou

seInflammation

IL-1120573uarr

FemaleW

istar

rats

[48]

A241m

2 g

Nanoceria

D55n

mInhalatio

nof

641m

gm

3for

24h48

hand14

days

Inflammation

IL-1120573uarrT


MDAuarrG

SHdarr

Wistar

rats

[49]

A30ndash

50m

2 g

Quantum

Dots

CdT

eNP

NA

164and

8mgLfor2

4hIm

mun

osup

pressio

nNA

Elliptio

ncomplanata

[50]

CdS

CdT

eNP

NA

510

and20

nmfor9

6hIm

mun

osup

pressio

nNA

Juvenilerainbo

wtro

ut[51]

SilicaN

anop

articles

Amorph

oussilica

NP

30and70

nmIntraperito

nealinjectionof

1mgmice

Inflammation

IL-5uarrIL-6uarrM

CP-1uarr

keratin

ocytec

hemoattractantuarr

FemaleB

ALB

c[52]

Amorph

oussilica

NP

mod

ificatedwith

carboxyl

grou

ps70

nmIntraperito

nealinjectionof

1mgmice

Supp

ressionof

inflammation

NA

Non

porous

nano

silicaN

P15nm

Intravenou

sinjectio

nsat

singled

osea

t50m

gkg

Inflammation

oxidatives

tress

ROSuarrT

NF-120572uarrN

Ouarr

MaleS

Drats

[53]

Polymer

Polysty

rene

NP

50nm

Intratracheal

administratio

nof

200120583

gmou

se

Anti-infl

ammation

immun

osup

pressio


Allergen

challengem

ice

[54]

Polysty

rene

beads(PS

B)coup

led

with

theimmun

odom

inant

myelin

proteolip

idprotein



)

500n

mintravenou

sinjectio

nof

approxim

ately9times109

microparticles

T-celltolerance


Peptide-indu

cedexperim

ental

autoim

mun

eenceph

alom

yelitisSJLJm

ice

[55]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Dendrim

er

Pan-DR-bind

ingepito

pe(PADRE

)-deriv

atized-dendrim

er(PDD)

NA

Intravenou

sinjectio

nwith

625

mgkgday

ofLA

mBat

aratio

of101

(PDDLAmB)

for10days

enhanced

adaptiv

eim

mun

ityIFN-120574uarr

FemaleB

ALB

cmice

inoculated

intraperito

neally

with

metacyclic

prom

astig

otes

ofLmajor

[56]

LipidNanop

articles

cSLN

-pDNA(a

DNAvaccine

harbou

ringtheL

donovaniA

2antig

enalon

gwith

Linfantum

cyste

inep

roteinases)com

plexes

241plusmn12nm

immun

ized

inthe


50120583gof

Qiagenpu

rified

pDNA

Enhanced

immun

ityRa

tioof

IFN-120574

IL-10uarr

Linfantum

prom

astig

otes

challenged

femaleB

ALB

cmice

[57]

MPL

AN

LP6ndash

25nm

intraperito

nealinjection

ionof

151020120583

gmou

seEn

hanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

CpGN

LPconstructs

6ndash25

nmintraperito

nealinjection

ionof

102040

or80120583gmou

se

Enhanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

Pegylated

liposom

aldo

xorubicin

(Doxil)

85ndash100

nmInfuse

inaccordance

with

thea

dministratio

nguidelineo

fDoxil

Hypersensitivity

reactio

nsoccurred

in45of

patie

nts

NA

Patie

ntsw

ithsolid

tumors

(119899=29)treated

with

Doxilfor

thefi

rsttim

e[59]













2O2-induced















70

fullerene [29]


19) was an
























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table1Im

mun

omod

ulationof

vario

usnano

particlesinnano

medicinea

pplications

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Carbon

nano

tube

MWCN

TL5ndash15120583m

Inhalatio

n5m

gm

3

6hday

14days

Immun

osup

pressio

nTG


MaleC

57BL

6[1718]

D10ndash

20nm

SWCN

TL1ndash3120583

mPh

aryn

gealaspiratio

n40

80120120583gmou

seInflammation

immun

osup

pressio

nTN


CP1uarr

FemaleB

ALB

candC5

7BL6

[19]

D1ndash4

nm

MWCN

TLseveral120583

mOroph

aryn

gealaspiratio

n1

2and4m

gkg

Inflammation

IL-33uarrC

CL3uarrC

CL11uarr

C57B

L6

[2021]

D125ndash25

nm

MWCN

TLseveral120583

mOroph

aryn

gealaspiratio

n4m

gkg

Inflammation


C57B

L6

[22]

D125ndash25

nm

MWCN

TL15plusmn5120583m

Intravenou

sly1m

gkg

Inflammation

IL-4uarrIL-33uarr

C57B

L6

[23]

D25plusmn5nm

MWCN

TL50120583m

Subcutaneous

00503and

05m

gtimes2mou

seAc

uteinfl

ammation


IFN-120574uarr

BALB

c[24]

D20ndash

30nm

MWCN

TL03ndash50120583m

Inhalatio

n100m

gm

3times6h

Hypersensitivity

PDGF-AAuarrT

GF-120573uarr

Allergicasthmam

ice

(C57BL

6)

[25]

D30ndash

50nm

SWCN

TL3ndash30120583m


6mou

seHypersensitivity


-120574uarr



(maleICR

)[26]

D67n

mGraph

ene

Graph

ene

4plusmn1120583m

2area

Intravenou

sly1m

gkg

Activ

ateTh

2im

mun

erespon


C57B

L6

[23]

2plusmn1nm

thick

Fullerene

C60

NA

Intravenou

sly50

ngm

ouse

Immun

osup

pressio

nSerum

histam

inedarrLyndarr

SykdarrR

OSdarr

MC-

depend

entm

odelof

anaphylaxis(C5

7BL6)

[16]

C60

NA

Intra-artic

ular

treatment

100120583Mw

eektimes8week

Immun

osup

pressio

nTN


Ratm

odelof

arthritis(fe

male

Sprague-Daw

leyrats)

[27]

C60

NA

Instillatio

n2m

gkg

Inflammation

IL-1uarrT


IFN-120574uarr

MaleICR

[2829]

Carboxyfullerene

NA

Periton

eum

andairp

ouch

40mgkg

Activ

ateimmun

esyste

mNA

C57B

L6

[30]

HydroxylatedC6

0NA


2120583gg

Immun

osup

pressio

nIL-11uarrelasta

se2genedarr

Fatheadminno

w[31]

C60

NA

Intraperito

nealinjection

05m


days

Immun

osup

pressio

nIFN-120574uarr

Tumor-bearin

gmice

(C57BL

6)

[14]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Goldnano

particles

PfMSP-1

19PvM

SP-1

19coated

GNPs

form

ulated

with

alum

17nm

Subcutaneously25

120583gmou

seIm

mun

ogenic

Antibod

ytiteruarr

BALB

c[15]

PfMSP-1

19PvM

SP-1

19coated

GNPs

17nm

Subcutaneously

25120583gmou

sePo

orim

mun

ogenic

NA

BALB

c[15]

Short-c

hain

PEG

mixed-m

onolayer

protectedgold

cluste

rslt5n


40120583Mtimes200120583

LIm

mun

ogenic

Antibod

ytiteruarr

BALB

cAnN

Hsd

[3233]

PEGcoated

GNP

13nm

Intravenou

sly0017085

or426

mgkg

Acuteinfl

ammation

MCP

-1C

CL-2uarr

MIP-1120572C

CL-3uarrM

IP-1120573uarr

RANTE

SCC



TNF-120572uarr

BALB

c[34]

GNPfunctio

nalized

with


cid

(MES

)orN

NN-

trim

ethylammon

iumethanethiol

(TMAT

)

15nm

Mediaexpo

sure

0016ndash

250p

pm

Activ

ateimmun

erespon

seInflammatory

respon

se


Zebrafish

embryos

[35]


40nm

Oroph

aryn

gealaspiratio

n08m

gkg

Hypersensitivity

MMP-9uarrM

IP-2uarrT

NF-120572darr

IL-6darr


LBc)

[36]

GNP

21nm

Intraperito

neallyinjection

785120583

gg

Antiflam

matory

TNF-120572mRN

AdarrIL-6mRN

Adarr

MaleC

57BL

6[37]


5nm

100n

molAu

kg

Antiflam

matory

IL-1120573darr

IL-1120573mod

elmice(male

C57B

L6)

[38]

Silver

Nanop

articles

AgN

P2218plusmn172nm

Inhalatio


3times

6hdaytimes5daysw

eektimes2

weeks

Immun

osup

pressio

nMalt1genedarrSem

a7ag

enedarr

C57B

L6

[39]

AgN

P5225plusmn2364nm


n35

or175m

gkg

once

every2

days

for5

weeks

Enhanceimmun

efunctio

nIL-1uarrIL-6uarrT

NF-120572uarrG

SHdarr

T-SO

DdarrM

DAuarrN

Ouarr

Wistar

rats

[40]

Agconjugated

tocore

nano

beads40

ndash50n

mIntradermally

Immun

ogenic


yuarrH-2Kb

C57B

L6

[41]

Magnetic

Nanop

articles

Iron

Oxide

NP

43nm


n(4

or20120583gtimes3)

Activ

ateimmun

erespon


OVA

-sensitized

mice

(BALB

c)

[4243]

Iron

Oxide

NP

587nm

Intravenou

slyle10mg

ironkg

Immun

osup

pressio


NF-120572darr

DTH

mice(maleB

ALB

c)

[44]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Iron

Oxide

NP

35plusmn14nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

OVA

-sensitized

mice

(BALB

c)

[45]

Intratracheally

4times100120583gmou

seHypersensitivity

IgEuarr

IL-4uarr

147plusmn48nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

Intratracheally

4times100120583gmou

seNosig

nificanteffect

NA

Nanoceria

Nanoceria

D8

nmOroph

aryn

gealinstillatio

nof

1030or

100120583

gmou

seInflammation


opon

tinuarr

C57B

L6

[46]

A44m

2 g

Nanoceria

20nm

Sing

leintratracheal


mgkg

Inflammation

NOdarrIL-12uarr

Specificp

atho

gen-fre

emale

Sprague-Daw

ley(H

la

SD-C

VF)

rats

[47]

Nanoceria

D20ndash

30nm


nat

50and150m

2 mou

seInflammation

IL-1120573uarr

FemaleW

istar

rats

[48]

A241m

2 g

Nanoceria

D55n

mInhalatio

nof

641m

gm

3for

24h48

hand14

days

Inflammation

IL-1120573uarrT


MDAuarrG

SHdarr

Wistar

rats

[49]

A30ndash

50m

2 g

Quantum

Dots

CdT

eNP

NA

164and

8mgLfor2

4hIm

mun

osup

pressio

nNA

Elliptio

ncomplanata

[50]

CdS

CdT

eNP

NA

510

and20

nmfor9

6hIm

mun

osup

pressio

nNA

Juvenilerainbo

wtro

ut[51]

SilicaN

anop

articles

Amorph

oussilica

NP

30and70

nmIntraperito

nealinjectionof

1mgmice

Inflammation

IL-5uarrIL-6uarrM

CP-1uarr

keratin

ocytec

hemoattractantuarr

FemaleB

ALB

c[52]

Amorph

oussilica

NP

mod

ificatedwith

carboxyl

grou

ps70

nmIntraperito

nealinjectionof

1mgmice

Supp

ressionof

inflammation

NA

Non

porous

nano

silicaN

P15nm

Intravenou

sinjectio

nsat

singled

osea

t50m

gkg

Inflammation

oxidatives

tress

ROSuarrT

NF-120572uarrN

Ouarr

MaleS

Drats

[53]

Polymer

Polysty

rene

NP

50nm

Intratracheal

administratio

nof

200120583

gmou

se

Anti-infl

ammation

immun

osup

pressio


Allergen

challengem

ice

[54]

Polysty

rene

beads(PS

B)coup

led

with

theimmun

odom

inant

myelin

proteolip

idprotein



)

500n

mintravenou

sinjectio

nof

approxim

ately9times109

microparticles

T-celltolerance


Peptide-indu

cedexperim

ental

autoim

mun

eenceph

alom

yelitisSJLJm

ice

[55]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Dendrim

er

Pan-DR-bind

ingepito

pe(PADRE

)-deriv

atized-dendrim

er(PDD)

NA

Intravenou

sinjectio

nwith

625

mgkgday

ofLA

mBat

aratio

of101

(PDDLAmB)

for10days

enhanced

adaptiv

eim

mun

ityIFN-120574uarr

FemaleB

ALB

cmice

inoculated

intraperito

neally

with

metacyclic

prom

astig

otes

ofLmajor

[56]

LipidNanop

articles

cSLN

-pDNA(a

DNAvaccine

harbou

ringtheL

donovaniA

2antig

enalon

gwith

Linfantum

cyste

inep

roteinases)com

plexes

241plusmn12nm

immun

ized

inthe


50120583gof

Qiagenpu

rified

pDNA

Enhanced

immun

ityRa

tioof

IFN-120574

IL-10uarr

Linfantum

prom

astig

otes

challenged

femaleB

ALB

cmice

[57]

MPL

AN

LP6ndash

25nm

intraperito

nealinjection

ionof

151020120583

gmou

seEn

hanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

CpGN

LPconstructs

6ndash25

nmintraperito

nealinjection

ionof

102040

or80120583gmou

se

Enhanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

Pegylated

liposom

aldo

xorubicin

(Doxil)

85ndash100

nmInfuse

inaccordance

with

thea

dministratio

nguidelineo

fDoxil

Hypersensitivity

reactio

nsoccurred

in45of

patie

nts

NA

Patie

ntsw

ithsolid

tumors

(119899=29)treated

with

Doxilfor

thefi

rsttim

e[59]













2O2-induced















70

fullerene [29]


19) was an
























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Goldnano

particles

PfMSP-1

19PvM

SP-1

19coated

GNPs

form

ulated

with

alum

17nm

Subcutaneously25

120583gmou

seIm

mun

ogenic

Antibod

ytiteruarr

BALB

c[15]

PfMSP-1

19PvM

SP-1

19coated

GNPs

17nm

Subcutaneously

25120583gmou

sePo

orim

mun

ogenic

NA

BALB

c[15]

Short-c

hain

PEG

mixed-m

onolayer

protectedgold

cluste

rslt5n


40120583Mtimes200120583

LIm

mun

ogenic

Antibod

ytiteruarr

BALB

cAnN

Hsd

[3233]

PEGcoated

GNP

13nm

Intravenou

sly0017085

or426

mgkg

Acuteinfl

ammation

MCP

-1C

CL-2uarr

MIP-1120572C

CL-3uarrM

IP-1120573uarr

RANTE

SCC



TNF-120572uarr

BALB

c[34]

GNPfunctio

nalized

with


cid

(MES

)orN

NN-

trim

ethylammon

iumethanethiol

(TMAT

)

15nm

Mediaexpo

sure

0016ndash

250p

pm

Activ

ateimmun

erespon

seInflammatory

respon

se


Zebrafish

embryos

[35]


40nm

Oroph

aryn

gealaspiratio

n08m

gkg

Hypersensitivity

MMP-9uarrM

IP-2uarrT

NF-120572darr

IL-6darr


LBc)

[36]

GNP

21nm

Intraperito

neallyinjection

785120583

gg

Antiflam

matory

TNF-120572mRN

AdarrIL-6mRN

Adarr

MaleC

57BL

6[37]


5nm

100n

molAu

kg

Antiflam

matory

IL-1120573darr

IL-1120573mod

elmice(male

C57B

L6)

[38]

Silver

Nanop

articles

AgN

P2218plusmn172nm

Inhalatio


3times

6hdaytimes5daysw

eektimes2

weeks

Immun

osup

pressio

nMalt1genedarrSem

a7ag

enedarr

C57B

L6

[39]

AgN

P5225plusmn2364nm


n35

or175m

gkg

once

every2

days

for5

weeks

Enhanceimmun

efunctio

nIL-1uarrIL-6uarrT

NF-120572uarrG

SHdarr

T-SO

DdarrM

DAuarrN

Ouarr

Wistar

rats

[40]

Agconjugated

tocore

nano

beads40

ndash50n

mIntradermally

Immun

ogenic


yuarrH-2Kb

C57B

L6

[41]

Magnetic

Nanop

articles

Iron

Oxide

NP

43nm


n(4

or20120583gtimes3)

Activ

ateimmun

erespon


OVA

-sensitized

mice

(BALB

c)

[4243]

Iron

Oxide

NP

587nm

Intravenou

slyle10mg

ironkg

Immun

osup

pressio


NF-120572darr

DTH

mice(maleB

ALB

c)

[44]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Iron

Oxide

NP

35plusmn14nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

OVA

-sensitized

mice

(BALB

c)

[45]

Intratracheally

4times100120583gmou

seHypersensitivity

IgEuarr

IL-4uarr

147plusmn48nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

Intratracheally

4times100120583gmou

seNosig

nificanteffect

NA

Nanoceria

Nanoceria

D8

nmOroph

aryn

gealinstillatio

nof

1030or

100120583

gmou

seInflammation


opon

tinuarr

C57B

L6

[46]

A44m

2 g

Nanoceria

20nm

Sing

leintratracheal


mgkg

Inflammation

NOdarrIL-12uarr

Specificp

atho

gen-fre

emale

Sprague-Daw

ley(H

la

SD-C

VF)

rats

[47]

Nanoceria

D20ndash

30nm


nat

50and150m

2 mou

seInflammation

IL-1120573uarr

FemaleW

istar

rats

[48]

A241m

2 g

Nanoceria

D55n

mInhalatio

nof

641m

gm

3for

24h48

hand14

days

Inflammation

IL-1120573uarrT


MDAuarrG

SHdarr

Wistar

rats

[49]

A30ndash

50m

2 g

Quantum

Dots

CdT

eNP

NA

164and

8mgLfor2

4hIm

mun

osup

pressio

nNA

Elliptio

ncomplanata

[50]

CdS

CdT

eNP

NA

510

and20

nmfor9

6hIm

mun

osup

pressio

nNA

Juvenilerainbo

wtro

ut[51]

SilicaN

anop

articles

Amorph

oussilica

NP

30and70

nmIntraperito

nealinjectionof

1mgmice

Inflammation

IL-5uarrIL-6uarrM

CP-1uarr

keratin

ocytec

hemoattractantuarr

FemaleB

ALB

c[52]

Amorph

oussilica

NP

mod

ificatedwith

carboxyl

grou

ps70

nmIntraperito

nealinjectionof

1mgmice

Supp

ressionof

inflammation

NA

Non

porous

nano

silicaN

P15nm

Intravenou

sinjectio

nsat

singled

osea

t50m

gkg

Inflammation

oxidatives

tress

ROSuarrT

NF-120572uarrN

Ouarr

MaleS

Drats

[53]

Polymer

Polysty

rene

NP

50nm

Intratracheal

administratio

nof

200120583

gmou

se

Anti-infl

ammation

immun

osup

pressio


Allergen

challengem

ice

[54]

Polysty

rene

beads(PS

B)coup

led

with

theimmun

odom

inant

myelin

proteolip

idprotein



)

500n

mintravenou

sinjectio

nof

approxim

ately9times109

microparticles

T-celltolerance


Peptide-indu

cedexperim

ental

autoim

mun

eenceph

alom

yelitisSJLJm

ice

[55]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Dendrim

er

Pan-DR-bind

ingepito

pe(PADRE

)-deriv

atized-dendrim

er(PDD)

NA

Intravenou

sinjectio

nwith

625

mgkgday

ofLA

mBat

aratio

of101

(PDDLAmB)

for10days

enhanced

adaptiv

eim

mun

ityIFN-120574uarr

FemaleB

ALB

cmice

inoculated

intraperito

neally

with

metacyclic

prom

astig

otes

ofLmajor

[56]

LipidNanop

articles

cSLN

-pDNA(a

DNAvaccine

harbou

ringtheL

donovaniA

2antig

enalon

gwith

Linfantum

cyste

inep

roteinases)com

plexes

241plusmn12nm

immun

ized

inthe


50120583gof

Qiagenpu

rified

pDNA

Enhanced

immun

ityRa

tioof

IFN-120574

IL-10uarr

Linfantum

prom

astig

otes

challenged

femaleB

ALB

cmice

[57]

MPL

AN

LP6ndash

25nm

intraperito

nealinjection

ionof

151020120583

gmou

seEn

hanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

CpGN

LPconstructs

6ndash25

nmintraperito

nealinjection

ionof

102040

or80120583gmou

se

Enhanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

Pegylated

liposom

aldo

xorubicin

(Doxil)

85ndash100

nmInfuse

inaccordance

with

thea

dministratio

nguidelineo

fDoxil

Hypersensitivity

reactio

nsoccurred

in45of

patie

nts

NA

Patie

ntsw

ithsolid

tumors

(119899=29)treated

with

Doxilfor

thefi

rsttim

e[59]













2O2-induced















70

fullerene [29]


19) was an
























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Iron

Oxide

NP

35plusmn14nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

OVA

-sensitized

mice

(BALB

c)

[45]

Intratracheally

4times100120583gmou

seHypersensitivity

IgEuarr

IL-4uarr

147plusmn48nm

Intratracheally

4times500120583gmou

seIntratracheally

4times250120583gmou

se

Immun

osup

pressio

nIgEdarr

IL-4darr

Intratracheally

4times100120583gmou

seNosig

nificanteffect

NA

Nanoceria

Nanoceria

D8

nmOroph

aryn

gealinstillatio

nof

1030or

100120583

gmou

seInflammation


opon

tinuarr

C57B

L6

[46]

A44m

2 g

Nanoceria

20nm

Sing

leintratracheal


mgkg

Inflammation

NOdarrIL-12uarr

Specificp

atho

gen-fre

emale

Sprague-Daw

ley(H

la

SD-C

VF)

rats

[47]

Nanoceria

D20ndash

30nm


nat

50and150m

2 mou

seInflammation

IL-1120573uarr

FemaleW

istar

rats

[48]

A241m

2 g

Nanoceria

D55n

mInhalatio

nof

641m

gm

3for

24h48

hand14

days

Inflammation

IL-1120573uarrT


MDAuarrG

SHdarr

Wistar

rats

[49]

A30ndash

50m

2 g

Quantum

Dots

CdT

eNP

NA

164and

8mgLfor2

4hIm

mun

osup

pressio

nNA

Elliptio

ncomplanata

[50]

CdS

CdT

eNP

NA

510

and20

nmfor9

6hIm

mun

osup

pressio

nNA

Juvenilerainbo

wtro

ut[51]

SilicaN

anop

articles

Amorph

oussilica

NP

30and70

nmIntraperito

nealinjectionof

1mgmice

Inflammation

IL-5uarrIL-6uarrM

CP-1uarr

keratin

ocytec

hemoattractantuarr

FemaleB

ALB

c[52]

Amorph

oussilica

NP

mod

ificatedwith

carboxyl

grou

ps70

nmIntraperito

nealinjectionof

1mgmice

Supp

ressionof

inflammation

NA

Non

porous

nano

silicaN

P15nm

Intravenou

sinjectio

nsat

singled

osea

t50m

gkg

Inflammation

oxidatives

tress

ROSuarrT

NF-120572uarrN

Ouarr

MaleS

Drats

[53]

Polymer

Polysty

rene

NP

50nm

Intratracheal

administratio

nof

200120583

gmou

se

Anti-infl

ammation

immun

osup

pressio


Allergen

challengem

ice

[54]

Polysty

rene

beads(PS

B)coup

led

with

theimmun

odom

inant

myelin

proteolip

idprotein



)

500n

mintravenou

sinjectio

nof

approxim

ately9times109

microparticles

T-celltolerance


Peptide-indu

cedexperim

ental

autoim

mun

eenceph

alom

yelitisSJLJm

ice

[55]


Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Dendrim

er

Pan-DR-bind

ingepito

pe(PADRE

)-deriv

atized-dendrim

er(PDD)

NA

Intravenou

sinjectio

nwith

625

mgkgday

ofLA

mBat

aratio

of101

(PDDLAmB)

for10days

enhanced

adaptiv

eim

mun

ityIFN-120574uarr

FemaleB

ALB

cmice

inoculated

intraperito

neally

with

metacyclic

prom

astig

otes

ofLmajor

[56]

LipidNanop

articles

cSLN

-pDNA(a

DNAvaccine

harbou

ringtheL

donovaniA

2antig

enalon

gwith

Linfantum

cyste

inep

roteinases)com

plexes

241plusmn12nm

immun

ized

inthe


50120583gof

Qiagenpu

rified

pDNA

Enhanced

immun

ityRa

tioof

IFN-120574

IL-10uarr

Linfantum

prom

astig

otes

challenged

femaleB

ALB

cmice

[57]

MPL

AN

LP6ndash

25nm

intraperito

nealinjection

ionof

151020120583

gmou

seEn

hanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

CpGN

LPconstructs

6ndash25

nmintraperito

nealinjection

ionof

102040

or80120583gmou

se

Enhanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

Pegylated

liposom

aldo

xorubicin

(Doxil)

85ndash100

nmInfuse

inaccordance

with

thea

dministratio

nguidelineo

fDoxil

Hypersensitivity

reactio

nsoccurred

in45of

patie

nts

NA

Patie

ntsw

ithsolid

tumors

(119899=29)treated

with

Doxilfor

thefi

rsttim

e[59]













2O2-induced















70

fullerene [29]


19) was an
























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table1Con

tinued

Nanom

aterial

Size

Expo

sure

routesdoses

Outcomes

Cytokineschem

okines

Animal

Reference

Dendrim

er

Pan-DR-bind

ingepito

pe(PADRE

)-deriv

atized-dendrim

er(PDD)

NA

Intravenou

sinjectio

nwith

625

mgkgday

ofLA

mBat

aratio

of101

(PDDLAmB)

for10days

enhanced

adaptiv

eim

mun

ityIFN-120574uarr

FemaleB

ALB

cmice

inoculated

intraperito

neally

with

metacyclic

prom

astig

otes

ofLmajor

[56]

LipidNanop

articles

cSLN

-pDNA(a

DNAvaccine

harbou

ringtheL

donovaniA

2antig

enalon

gwith

Linfantum

cyste

inep

roteinases)com

plexes

241plusmn12nm

immun

ized

inthe


50120583gof

Qiagenpu

rified

pDNA

Enhanced

immun

ityRa

tioof

IFN-120574

IL-10uarr

Linfantum

prom

astig

otes

challenged

femaleB

ALB

cmice

[57]

MPL

AN

LP6ndash

25nm

intraperito

nealinjection

ionof

151020120583

gmou

seEn

hanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

CpGN

LPconstructs

6ndash25

nmintraperito

nealinjection

ionof

102040

or80120583gmou

se

Enhanced

immun

ostim

ulatory

IL-6uarrT

NF-120572uarrM

IP-1120572uarr

FemaleB

ALB

cmice

[58]

Pegylated

liposom

aldo

xorubicin

(Doxil)

85ndash100

nmInfuse

inaccordance

with

thea

dministratio

nguidelineo

fDoxil

Hypersensitivity

reactio

nsoccurred

in45of

patie

nts

NA

Patie

ntsw

ithsolid

tumors

(119899=29)treated

with

Doxilfor

thefi

rsttim

e[59]













2O2-induced















70

fullerene [29]


19) was an
























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials















2O2-induced















70

fullerene [29]


19) was an
























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials















70

fullerene [29]


19) was an
























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials

























OO

HNON

AM001

N

AM002 AM003NHNHNH

NH NH NH

AM004 AM005N

AM006

OO

AM007 AM008

OO

Fmoc5 6 7 8 9 10 11 12

HDe-Fmoc 13 14 15 16 17 18 19 20O

AC00121 29 37 45 53 61 69 77

O

AC00222 30 38 46 54 62 70 78

OAC003

23 31 39 47 55 63 71 79O

AC00424 32 40 48 56 64 72 80

O

ClAC005

25 33 41 49 57 65 73 81

SOOAC006

26 34 42 50 58 66 74 82

SOO

AC00727 35 43 51 59 67 75 83

SOO

AC00828 36 44 52 60 68 76 84

R2

R1

R9984001

R1R9984001N-

R2- O2N

O2N

F3C

(a)

AM008AM007

AM006AM005

AM004

AM003AM002

AM001

AC008AC007

AC006AC005

AC004AC003

R2

R1

AC002AC001

De-FmocFmoc

Mul

tiass

ay sc

ore

400

300

200

100

0

(b)











Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials












Prostaglandin IL-10

T cell

Th1 cellTh2 cell

B cell

IL-4IL-2 IL-10



IFN-120574

CD4 T cell


Different NPs

ROS

Inflammation

TNF-120572 IL-1120573IL-6 IL-8

MCs )






Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Cytoskeleton damage

Necrosis

ROS

TNF-120572

TNF-120572

TNF receptor

ROCK


Filamental actin

kinase

PP

P

PP

P

P

P

TLR4

RIP1RIP3

GO






6 Conclusion



Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Abbreviations





Acknowledgments


References































































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials















































































2andTiO

2














































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



review article immunomodulation of nanoparticles...

Documents