Gold Nanoparticle-Based Colorimetric Strategies For Chemical and Biological Sensing Applications

nanomaterials
Review
Gold Nanoparticle-Based Colorimetric Strategies for
Chemical and Biological Sensing Applications
Chia-Chen Chang 1, * , Chie-Pein Chen 2 , Tzu-Heng Wu 3 , Ching-Hsu Yang 3 , Chii-Wann Lin 1,3,4
and Chen-Yu Chen 2, *
1 Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute,
Hsinchu 310, Taiwan; cwlinx@ntu.edu.tw
2 Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei 104, Taiwan;
cpchen@mmh.org.tw
3 Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University,
Taipei 106, Taiwan; aresation@gmail.com (T.-H.W.); d02945009@ntu.edu.tw (C.-H.Y.)
4 Department of Biomedical Engineering, National Taiwan University, Taipei 106, Taiwan
* Correspondence: cc.chang@itri.org.tw (C.-C.C.); f122481@mmh.org.tw (C.-Y.C.); Tel.: +886-2543-3535

Received: 13 May 2019; Accepted: 3 June 2019; Published: 6 June 2019
Abstract: Gold nanoparticles are popularly used in biological and chemical sensors and their
applications owing to their fascinating chemical, optical, and catalytic properties. Particularly, the use
of gold nanoparticles is widespread in colorimetric assays because of their simple, cost-effective
fabrication, and ease of use. More importantly, the gold nanoparticle sensor response is a visual change
in color, which allows easy interpretation of results. Therefore, many studies of gold nanoparticle-based
colorimetric methods have been reported, and some review articles published over the past years.
Most reviews focus exclusively on a single gold nanoparticle-based colorimetric technique for one
analyte of interest. In this review, we focus on the current developments in different colorimetric assay
designs for the sensing of various chemical and biological samples. We summarize and classify the
sensing strategies and mechanism analyses of gold nanoparticle-based detection. Additionally, typical
examples of recently developed gold nanoparticle-based colorimetric methods and their applications
in the detection of various analytes are presented and discussed comprehensively.
Keywords: gold nanoparticle; colorimetric assay; aggregation of AuNPs; etching of AuNPs; growth
of AuNPs; nanoenzyme
1. Introduction
Simple and convenient technologies for the identification of chemical and biological species
are of great significance in environmental monitoring, public health, and disease diagnosis [1,2].
However, detecting these chemical and biological species rapidly and cost-effectively with high
sensitivity and specificity is challenging. Traditional sensing techniques, such as chromatography,
electrochemistry, field-effect transistors, surface plasmonic resonance sensors, and microgravimetric
methods often require relatively expensive, cumbersome instruments and a skilled professional to
operate them in order to detect the various targets. For home testing or on-site analysis, there
is still scope for improvement in these techniques [3–6]. Compared with the various traditional
detection methods, colorimetric assays are extremely attractive due to their convenience, simplicity,
and cost-effectiveness [7]. Moreover, the colorimetric response is easy to monitor with the naked eye
without any sophisticated instrumentation; this assay is thus suitable for on-site detection [8].
Gold nanoparticle (AuNP)-based colorimetric sensors are of particular interest due to the several
unique features of gold nanomaterials, such as complex optical properties, controllable size, and catalytic
Nanomaterials 2019, 9, 861; doi:10.3390/nano9060861 www.mdpi.com/journal/nanomaterials

Nanomaterials 2019, 9, x FOR PEER REVIEW 2 of 24
Nanomaterials 2019, 9, 861 2 of 24
catalytic properties [9], and the synthesis of AuNPs is efficient and straightforward [10]. Most
importantly,
properties [9],the andversatile surfaceofchemistry
the synthesis AuNPs is of AuNPs
efficient andprovides a significant
straightforward [10]. linkage capability
Most importantly,
toward a wide
the versatile range
surface of molecular
chemistry of AuNPs probes witha significant
provides thiol groups for the
linkage functional
capability toward conjugation
a wide range andof
detection of chemical and biological targets [11–14]. Each of these AuNP features
molecular probes with thiol groups for the functional conjugation and detection of chemical and biological has motivated
significant efforts
targets [11–14]. Eachforofthe development
these AuNP features of ahasnew generation
motivated of sensing
significant effortsstrategies with enhanced
for the development of a
sensitivity, specificity,
new generation andstrategies
of sensing stability. with
In theenhanced
last two sensitivity,
decades, AuNP developments
specificity, have
and stability. Ingenerated
the last two a
dramatic increase in innovative colorimetric approaches for the efficient detection
decades, AuNP developments have generated a dramatic increase in innovative colorimetric approaches of nucleic acids
[15–17], proteins
for the efficient [18–20],of
detection and smallacids
nucleic molecules
[15–17],[21–23].
proteins [18–20], and small molecules [21–23].
We believe that a short review of the recent developments
We believe that a short review of the recent developments (2014–2018) (2014–2018)
in AuNP-based in AuNP-based
colorimetric
colorimetric assays is
assays is necessary tonecessary to facilitate
facilitate further further
research intoresearch into
this topic, butthis topic, but
hundreds of hundreds of relevant
relevant papers from
papers
the pastfrom
fivethe pastare
years five years
left out.areTheleft out. Theofpurpose
purpose of this
this review review
is to is to
briefly briefly introduce
introduce the new
the new progress
progress in areasfrom
in areas ranging ranging
novelfrom
sensingnovel sensing
concepts andconcepts and signal amplification
signal amplification strategies for
strategies for representative
representative sensingThe
sensing applications. applications.
discussion is The discussion
organized is organized
by the by the type
type of AuNP-based of AuNP-based
colorimetric sensors
colorimetric
(summarized sensors (summarized
in Figure 1), startinginwith
Figure 1), starting with aggregation-based
aggregation-based sensors followed by sensors followed
etching-, growth-,by
etching-, growth-, and nanozyme-based sensors. Finally, future challenges
and nanozyme-based sensors. Finally, future challenges and perspectives for the development of goldand perspectives for the
development of goldcolorimetric
nanomaterial-based nanomaterial-based
analyses colorimetric analyses will be discussed.
will be discussed.
Figure 1. The summary of different types of gold nanomaterial-based colorimetric sensors.

Figure 1. The summary of different types of gold nanomaterial-based colorimetric sensors.
2. Aggregation-Based Colorimetric Assays
2. Aggregation-Based Colorimetric Assays
Because AuNPs possess unique localized surface plasmon resonance (LSPR) properties with high
molarBecause AuNPs
extinction possessthey
coefficients, unique
show localized surface plasmon
size-dependent, resonance
distinct color (LSPR)
changes. properties
Generally, with
a colloidal
high molar extinction coefficients, they show size-dependent, distinct color
solution of 20 nm AuNPs has a wine-red color, and the LSPR band of the 20 nm AuNPs occurs changes. Generally, a
colloidal solution of
at approximately 52020nm.nm The
AuNPs has a wine-red
aggregation of AuNPscolor, and in
results thea LSPR
large band of the
red-shift 20 nm
of the LSPR AuNPs
peak,
occurs at approximately 520 nm. The aggregation of AuNPs results in a large red-shift
accompanied by a characteristic color change from red to blue [24]. Therefore, aggregation-based of the LSPR
peak, accompanied
colorimetric assays by
have a characteristic
wide-rangingcolor change
sensing from redin
applications toproteins
blue [24]. Therefore,
[25], aggregation-
small molecules [26],
based colorimetric assays have wide-ranging sensing applications in proteins [25], small
inorganic ions [27,28], enzyme activities [29], and oligonucleotides [30]. Currently, these colorimetric molecules
[26],
assaysinorganic ions [27,28],
can be divided into twoenzyme
systems:activities [29],label-free.
labeled and and oligonucleotides [30]. Currently, these
colorimetric assays can be divided into two systems: labeled and label-free.
2.1. Labeled Detection Methods

2.1. Labeled Detection Methods

The labeled method directly attaches ligands such as DNA, aptamers, peptides, or antibodies
ontoThe labeled
AuNPs method
through directly linkages
chemical attaches ligands
prior to such as DNA,
detection. aptamers, peptides,
Ligand-modified AuNPs or have
antibodies
higher
onto
stericAuNPs
and through chemical interparticle
hydration-based linkages priorrepulsions
to detection. andLigand-modified
are more stable AuNPs
at highhaveionic
higher steric
strength
and hydration-based
conditions than bareinterparticle
AuNPs, which repulsions and areand
are unstable moreundergo
stable ataggregation
high ionic strengthdue to conditions than
the salt-induced
bare AuNPs,
screening which
effect. are unstable
However, and undergo
the controlled aggregation
aggregation due to
of AuNPs in the salt-induced
label-based screening
colorimetric effect.
strategies
However, the controlled
can be achieved aggregation
by cross-linking, of AuNPs in label-based
non-cross-linking, colorimetric
or destabilization strategies can be achieved
aggregation.
by cross-linking, non-cross-linking, or destabilization aggregation.
2.1.1. Cross-Linking Aggregation
2.1.1. Cross-Linking Aggregation
In cross-linking strategies, AuNP aggregation is induced by the controlled assembly of ligand-
In cross-linking
functionalized AuNPs strategies,
with the AuNP aggregation
formation is induced by
of intermolecular bondsthe (such
controlled assembly ofor
as H-bonding
ligand-functionalized
hydrophobic interactions), AuNPswhich with overpower
the formation of intermolecular
the interparticle bonds
repulsive (such
forces as H-bonding
(such or
as electrostatic
hydrophobic interactions), which overpower the interparticle repulsive
repulsion). Peptide-functionalized AuNPs have been developed as biological recognition probes for forces (such as electrostatic
repulsion).
cross-linking Peptide-functionalized
methods in colorimetric AuNPsdiagnoses
have been [31–35].
developed as biologicaletrecognition
Chandrawati al. utilized probes for
peptide-
cross-linking methods in colorimetric diagnoses [31–35]. Chandrawati et
conjugated AuNPs for monitoring the concentration of blood coagulation Factor XIII, which requires al. utilized peptide-conjugated
AuNPs
thrombin for monitoring
and Ca2+ forthe concentration
activation of blood
[36]. The coagulation
peptides Factor XIII,
were terminated inwhich requires
glutamine thrombin
or lysine and
residues,
Ca 2+ for activation
allowing them to[36]. The peptides
be linked by the were terminated
formation of aninamide
glutamine
bondorinlysine residues,of
the presence allowing them toXIII.
active Factor be
linked by the formation of an amide bond in the presence of active Factor XIII.
Thus, this cross-linking reaction causes a notable decrease in interparticle distances, which results in Thus, this cross-linking
reaction causes a notable
the aggregation of AuNPs. decrease
Usinginainterparticle distances,
similar approach, which
Retout results
et al. in the aggregation
developed of AuNPs.
a one-step method for
Using a similar approach, Retout et al. developed a one-step method for
the rapid detection of oncoprotein Mdm2 (Figure 2), which is a p53- and p14-binding protein and the rapid detection of oncoprotein
Mdm2
which(Figure
may act 2), as
which is a p53- of
a regulator and p14-binding
these protein protein
functions and[37].
which may act
Hence, theas a regulator
AuNPs wereofmodified
these protein
with
functions
the peptides [37]. ofHence,
proteinsthep53
AuNPsand were modified
p14. After with theof
the addition peptides
Mdm2,of theproteins p53 and
aggregation p14.AuNPs
of the After the
was
addition of Mdm2, the aggregation of the AuNPs was driven by the formation
driven by the formation of a ternary complex of Mdm2, p53, and p14, and the color of the solution of a ternary complex of
Mdm2, p53, and p14, and the color of the solution changed from red to blue.
changed from red to blue. In addition to protein detection, Yang et al. reported the monitoring of In addition to protein detection,
Yang 2+ and As3+ by the modification of peptide A3 (AYYSGAPPMPPF)
Hg2+etandal. reported
As3+ by the the monitoring
modification of Hg
of peptide A3 (AYYSGAPPMPPF) to AuNPs [38]. The metal ions
toinduced
AuNPs [38]. The metal ions induced the assembly
the assembly of the AuNPs as the interparticle of the AuNPs as the interparticle
distances changed due distances changed due
to the complexation
toofthe complexation of the metal ions with the peptide A3. Elsewhere, Ding
the metal ions with the peptide A3. Elsewhere, Ding et al. used peptide-immobilized AuNPs for et al. used peptide-immobilized
AuNPs for theofdetection
the detection of trypsin
trypsin [39]. Substrate [39].peptides
Substrate peptides (YHPQMNPYTKAGGGC)
(YHPQMNPYTKAGGGC) triggered thetriggered the
cross-linking
cross-linking aggregation of AuNPs through their cysteine and lysine residues
aggregation of AuNPs through their cysteine and lysine residues and the hydrolysis of the substrates and the hydrolysis of the
substrates
by trypsin byinhibited
trypsin inhibited the aggregation
the aggregation of AuNPs. of AuNPs. Using
Using this this method,
method, they reported
they reported a detection
a detection limit of
limit of 0.5 nM
0.5 nM for trypsin. for trypsin.
Figure 2. The schematic representation of the detection of Mdm2 using two peptide aptamer-
Figure 2. TheAuNPs.
functionalized schematic
Afterrepresentation
the addition ofofMdm2,
the detection of Mdm2
the aggregation of theusing
AuNPstwowas
peptide
drivenaptamer-
by the
functionalized
formation AuNPs.
of a ternary After the
complex addition
of Mdm2, of Mdm2,
p53, and p14,the
andaggregation
the color ofofthe
thesolution
AuNPschanged
was driven
frombyred
the
formation of a ternary complex of Mdm2, p53, and p14, and the color
to blue. Reproduced with permission from [37]. American Chemical Society, 2017.of the solution changed from
red to blue. Reproduced with permission from [37]. American Chemical Society, 2017.
Other ligands such as nucleic acids [40,41], aptamers [42,43], and antibodies [44,45] have been
widely used to stabilize and functionalize AuNPs for the development of colorimetric
immunosensors. For example, Lesniewski et al. modified the AuNPs using antibodies for the one-
Other ligands such as nucleic acids [40,41], aptamers [42,43], and antibodies [44,45] have4 been
Nanomaterials 2019, 9, x FOR PEER REVIEW of 24
widely used to stabilize and functionalize AuNPs for the development of colorimetric immunosensors.
For detection
step example, of Lesniewski
the virus etT7 al. modified the
bacteriophage AuNPs
[46]. using antibodies
This method showed afor fastthe one-step
response timedetection
and a
of the virus T7 bacteriophage [46]. This method showed a fast response
comparable sensitivity compared to the standard plaque test. Goux et al. introduced a new cross- time and a comparable
sensitivity
linking compared
strategy (Figureto 3)
thethat
standard
relied plaque
on the test. Goux et
formation of al. introduced
kissing a newfor
complexes cross-linking strategy
sensing adenosine
(Figure 3)[47].
molecules thatKissing
relied on the formation
complexes occur of kissing complexes
in RNA–RNA for sensing
interactions adenosine
which allow for themolecules
assembly[47].of
Kissing complexes occur in RNA–RNA interactions which allow for the assembly
complementary loop domains through Watson–Crick base pairing [48]. In this study, they designed of complementary
aloop domains through
target-responsive Watson–Crick
kissing base pairing
aptamer, called [48]. In
aptaswitch, this study,
which has anthey designed a target-responsive
adenosine-binding region and
akissing
kissingaptamer,
region for called aptaswitch,
binding to another which
RNAhas an(aptakiss).
loop adenosine-binding regionof
In the presence andthea target,
kissingadenosine
region for
binding to another RNA loop (aptakiss). In the presence of the target,
specifically bound to its aptamer and changed the aptamer conformation from a random-coil adenosine specifically bound
to its aptamer
structure and changedstructure,
to a hairpin-like the aptamer conformation
thereby generating fromthea aptaswitch.
random-coilThen,structure
the to a hairpin-like
aptakiss could
structure, thereby generating the aptaswitch. Then, the aptakiss could establish a
establish a specific loop-loop interaction with the aptaswitch, resulting in the cross-liking aggregation specific loop-loop
ofinteraction
AsNPs and with the aptaswitch,
a red-to-purple resulting
color change. in Due
the cross-liking
to the variety aggregation
of hairpinof AsNPs probes
aptamer and a red-to-purple
and kissing
color change.
motifs, Due to
this strategy the variety
opens of hairpinfor
an opportunity aptamer probes
developing and kissing
further motifs,sensing
colorimetric this strategy opens an
platforms.
opportunity for developing further colorimetric sensing platforms.
Figure 3. (a) The schematic illustration of the formation of an aptamer kissing complex. The loop-loop
Figure 3. (a) The schematic illustration of the formation of an aptamer kissing complex. The loop-loop
interaction is shown in blue. (b) The principle of the cross-linking aggregation of AuNPs induced
interaction is shown in blue. (b) The principle of the cross-linking aggregation of AuNPs induced by
by the aptamer kissing complex. Reproduced with permission from Reference [47]. Royal Society of
the aptamer kissing complex. Reproduced with permission from Reference [47]. Royal Society of
Chemistry, 2017.
Chemistry, 2017.
Guo et al. [49] introduced the concept of asymmetrical DNA–AuNP oriented aggregation.
UnlikeGuoconventional
et al. [49] introduced
cross-linkingthe concept of
aggregation asymmetrical
methods that form DNA–AuNP oriented
large nanoparticle aggregation.
aggregates, Guo
Unlike conventional
et al. formed AuNPcross-linking
dimers, which aggregation
effectivelymethods
improvedthatthe
form large nanoparticle
long-term stability ofaggregates,
AuNPs. Due Guoto
eta al. formed AuNP
remarkable decreasedimers,
in thewhich effectively
interparticle gapimproved
caused bythethelong-term
AuNP dimers,stability
thisofmethod
AuNPs.provided
Due to aa
remarkable
100-fold widerdecrease
dynamic in the interparticle
range of detectiongapandcaused by thelower
a 10,000-fold AuNP dimers,
limit this method
of detection provided
(LOD) as compared a
100-fold wider dynamic range of detection and a 10,000-fold lower limit of detection
with conventional colorimetric sensors. In addition to DNA detection, this oriented aggregation has (LOD) as
compared
been used with
for theconventional colorimetric
analysis of melamine sensors. acid
[50], aspartic In addition to DNA detection,
[51], microcystin-LR this oriented
[52] and nitrite ions [53].
aggregation has beenaggregation
Cross-linking used for the analysis
methodsof melamine
offer a [50], aspartic colorimetric
convenient acid [51], microcystin-LR [52]
assay platform.
and nitrite ions [53].
Nevertheless, the sensitivity is limited to the nanomolar or subnanomolar levels due to the lack of
Cross-linking
amplification. In most aggregation methods offer
cases, the concentrations a convenient
of molecular biomarkers colorimetric assay platform.
are found in picomolar levels in
Nevertheless, the sensitivity
healthy individuals; therefore, is limited
these to the
markers arenanomolar
undetectableorbysubnanomolar levels due to
cross-linking aggregation. To the lack the
improve of
amplification. In most cases, the concentrations of molecular biomarkers are found
sensing performance, various signal amplification methods have been rationally designed and combined in picomolar
levels in healthy individuals; therefore, these markers are undetectable by cross-linking aggregation.
To improve the sensing performance, various signal amplification methods have been rationally
designed and combined with the cross-linking aggregation, including enzyme-aided signal
amplification (e.g., exonuclease [54,55], nicking endonucleases [56,57], and polymerases [41,58]) and
enzyme-free
with amplification
the cross-linking (e.g., hybridization
aggregation, chain reaction
including enzyme-aided signal[59,60] and catalytic
amplification hairpin assembly
(e.g., exonuclease [54,55],
[61,62]) strategies. With
nicking endonucleases the use
[56,57], and of these amplification
polymerases [41,58]) andapproaches,
enzyme-freethe sensitivity(e.g.,
amplification hashybridization
reached the
required levels
chain reaction of sensitivity
[59,60] and catalyticandhairpin
enabled picomolar
assembly andstrategies.
[61,62]) even attomolar
With thedetection capabilities
use of these amplification for
satisfactory
approaches, thediagnostic tests.
sensitivity has reached the required levels of sensitivity and enabled picomolar and even
attomolar detection capabilities for satisfactory diagnostic tests.
2.1.2. Non-Cross-Linking Aggregation
2.1.2. Non-Cross-Linking Aggregation
Double-stranded DNA (ds)-meditated AuNP assembly at high ionic strength was demonstrated
Double-stranded
by Maeda’s group [63]. DNA When(ds)-meditated
the AuNPsAuNP assembly with
are modified at high ionic strength was
single-stranded DNA demonstrated
(ssDNA), the by
Maeda’s group
dispersion [63].
of the When the AuNPs
ssDNA–AuNP complexare modified with single-stranded
in an aqueous medium of high DNAionic(ssDNA),
strengththe
is dispersion
stable due
of the
to ssDNA–AuNP
interparticle complexand
electrostatic in ansteric
aqueous mediumbetween
repulsion of high ionic strength is stable due
the ssDNA-modified to interparticle
AuNPs (ssDNA-
electrostatic and steric repulsion between the ssDNA-modified AuNPs
AuNPs). The formation of dsDNA–AuNP complexes results in a spontaneous aggregation of the (ssDNA-AuNPs). The formation
of dsDNA–AuNP
AuNPs within severalcomplexes
minutes, results
and ina ared-to-purple
spontaneous color aggregation
change.ofThisthe AuNPs within
transition reduces several
the
minutes, andinteraction
electrostatic a red-to-purple
between color change. This
nanoparticles transition
because reduces
the rigid the electrostatic
structures interaction
of the duplexes favor
between with
binding nanoparticles becauseMoreover,
counter cations. the rigid duplexes
structureslowerof the theduplexes
entropicfavor
effect,binding with counter
which decreases the
cations.
steric Moreover,
repulsion duplexes
[64,65]. Notably,lower thethe entropic effect, with
dsDNA–AuNPs which decreases the
a single-pair steric repulsion
mismatch [64,65].
at the terminal
Notably, significantly
position the dsDNA–AuNPs increasewiththe acolloidal
single-pair mismatch
stability of theatAuNPs
the terminal positionthe
and prevent significantly increase
non-cross-linking
the colloidal stability
aggregation. Based onofthis the finding,
AuNPs and prevent dispersion
the unique the non-cross-linking
behavior ofaggregation.
dsDNA–AuNPs Based hasonbeen
this
finding, the unique
successfully applieddispersion
in the rapid behavior of dsDNA–AuNPs
colorimetric detection of has beentargets
various successfully
[66,67].applied in the rapid
In addition, these
colorimetric
colloidal detection
behaviors areoffound
various in targets
different [66,67]. In addition,
sizes (5–300 nm) and these colloidal
shapes behaviors
(sphere, are found
rod, and triangle;in
different
Figure 4)sizes (5–300 nm) and
of nanoparticles shapes (sphere,
originating from the rod, and triangle;
multiple blunt-endFigure 4) of nanoparticles
stacking interaction tooriginating
dominate
frominterparticle
the the multipleattractive
blunt-end stacking
forces interaction to dominate the interparticle attractive forces [68,69].
[68,69].
Figure 4. The different colloidal behaviors of ssDNA-labeled gold nanospheres,

nanospheres, nanorods
nanorods (AuNRs),
(AuNRs),
and nanotriangles in aa moderately
moderately high
high ionic
ionic strength
strength medium.
medium. Double-headed arrows indicate
unpaired mononucleotides. Reproduced with permission from Reference [68]. Wiley,
Wiley, 2015.
2015.
Currently, DNA
Currently, DNA hybridization
hybridization using
using ssDNA–AuNPs
ssDNA–AuNPs has has been
been explored
explored byby both
both cross-linking
cross-linking
and non-cross-linking methods and the rapidity of the solution color change of the two colorimetric
and non-cross-linking methods and the rapidity of the solution color change of the two colorimetric
strategies were
strategies were compared.
compared. In In aa large
large number
number of of target
target DNAs,
DNAs, the
the non-cross-linking
non-cross-linking aggregation
aggregation
occurred significantly
occurred significantlyfaster than
faster with
than the the
with cross-linking aggregation.
cross-linking In contrast,
aggregation. when awhen
In contrast, small number
a small
number of DNA was provided, the non-cross-linking aggregation showed a much slower color
of DNA was provided, the non-cross-linking aggregation showed a much slower color change than
change than the cross-linking aggregation [70]. This study by Maeda’s group will serve as a guide to
the cross-linking aggregation [70]. This study by Maeda’s group will serve as a guide to help future
help future researchers choose the appropriate aggregation strategies for designing DNA–AuNP-
researchers choose the appropriate aggregation strategies for designing DNA–AuNP-based colorimetric
based colorimetric sensors under given conditions.
sensors under given conditions.
Likewise, non-cross-linking aggregation methods also suffer from sensitivity issues. To
Likewise, non-cross-linking aggregation methods also suffer from sensitivity issues. To overcome
overcome this limitation, Maeda’s group developed a plasmonic colloidal nanosensor through the
this limitation, Maeda’s group developed a plasmonic colloidal nanosensor through the combination
combination of signal amplification using catalytic DNA hairpin self-assembly and signal
of signal amplification using catalytic DNA hairpin self-assembly and signal transduction using the
transduction using the salt-induced aggregation of DNA-modified AuNPs (Figure 5) [71]. The
salt-induced aggregation of DNA-modified AuNPs (Figure 5) [71]. The detection limit was 130-fold
detection limit was 130-fold greater than that of previously reported methods. In this study, they
greater than that of previously reported methods. In this study, they employed an anti-Cry j 2 DNA
employed an anti-Cry j 2 DNA aptamer as a molecular recognition unit, which accounted for the lack
aptamer as a molecular recognition unit, which accounted for the lack of false responses to non-target
of false responses to non-target allergen proteins. In addition, the assay was robust enough to enable
allergen proteins. In addition, the assay was robust enough to enable the detection of Cry j 2 spiked
the detection of Cry j 2 spiked soil solutions without any interference from the contaminants. This
soil solutions without any interference from the contaminants. This method could be readily applied
method could be readily applied to the visual detection of various proteins by using appropriate
to the visual detection of various proteins by using appropriate aptamers as recognition units.
aptamers as recognition units.
Figure 5. A non-crosslink aggregation assay showing the principle of catalytic target recycling. (a) The
Figure 5. A non-crosslink aggregation assay showing the principle of catalytic target recycling. (a)
Cry j 2 target catalyzes the reaction of the hairpins H1 and H2 into a duplex structure, to produce an
The Cry j 2 target catalyzes the reaction of the hairpins H1 and H2 into a duplex structure, to produce
H1/H2 duplex after each cycle. (b) In the presence of Cry j 2, the H1/H2 duplex forms a three-way DNA
an H1/H2 duplex after each cycle. (b) In the presence of Cry j 2, the H1/H2 duplex forms a three-way
junction with P1. Thus, the color does not change due to the colloidal stabilization of ssDNA–AuNPs.
DNA junction with P1. Thus, the color does not change due to the colloidal stabilization of ssDNA–
(c) In contrast, the red-to-purple color change is caused by salt-induced non-cross-linking aggregation
AuNPs. (c) In contrast, the red-to-purple color change is caused by salt-induced non-cross-linking
of dsDNA−AuNPs in the absence of Cry j 2. Reproduced with permission from Reference [71].
aggregation of dsDNA−AuNPs in the absence of Cry j 2. Reproduced with permission from Reference
American Chemical Society, 2019.
[71]. American Chemical Society, 2019.
2.1.3. Destabilization-Induced Aggregation
2.1.3. Destabilization-Induced Aggregation
Apart from the non-cross-linking aggregation strategies described above, the change of ligand
lengthApart from the
or structure onnon-cross-linking
the AuNP surfaceaggregation
can also be strategies described
used to control above, aggregation.
the AuNP the change ofInligand
the
length or structure on the AuNP surface can also be used to control the AuNP aggregation.
destabilization-induced aggregation strategies, AuNP aggregation is induced by the controlled In the
destabilization-induced aggregation strategies, AuNP aggregation is induced by the controlled
loss of electrosteric stabilizations when a part of the ligand is cleaved. For example, McVey et al. loss
of electrosteric
reported a method stabilizations when a part
to detect pathogenic of the ligand
bacterial DNA byis cleaved. For example,
using RNase McVey
H-controlled et al. reported
aggregation of
a method to detect pathogenic bacterial DNA by using RNase H-controlled aggregation
AuNPs. RNA-functionalized AuNPs (RNA–AuNPs) were cleaved by RNase H when the formation of AuNPs.
RNA-functionalized AuNPs (RNA–AuNPs) were cleaved by RNase H when the formation of DNA–
RNA hybridization [72]. Because RNase H catalyzed the cleavage of RNA in a DNA–RNA complex,
the DNA target could be liberated and hybridize with other RNA probes on the AuNPs. Although

of DNA–RNA hybridization [72]. Because RNase H catalyzed the cleavage of RNA in a DNA–RNA
complex,
this strategythe DNA
using target couldis be
RNA–AuNPs liberated
simple and hybridize
and provides with otherthe
high sensitivity, RNA probes onconditions
experimental the AuNPs.
Although
should this strategy
be carefully using
chosen RNA–AuNPs
because RNA is a is simple
labile and provides
material high sensitivity,
that degrades extremely the experimental
rapidly, which
conditions should be carefully chosen because RNA is a labile material that degrades
makes it difficult material with which to work. Similarly, Aldewachi optimized a colorimetric assay extremely rapidly,
which makes it difficult material with which to work. Similarly, Aldewachi optimized
for the real-time monitoring of dipeptidyl peptidase-IV activity based on the hydrolysis of peptide a colorimetric
assay for the AuNPs
functionalized real-timeinmonitoring
the presence of of
dipeptidyl
an enzyme peptidase-IV
(Figure 6) activity
[73,74]. based
Zhangon the utilized
then hydrolysisthisof
peptide functionalized AuNPs in the presence of an enzyme (Figure 6) [73,74].
strategy for the real-time measurement of lipase kinetics, using Tween 20 as a stabilizing substrateZhang then utilized
forthis strategy
lipase. for the
Firstly, thereal-time
additionmeasurement
of Tween 20of canlipase kinetics,
adsorb onto using Tween of
the surface 20 AuNPs
as a stabilizing
to preventsubstrate
the
for lipase. Firstly, the addition of Tween 20 can adsorb onto the surface of
aggregation of AuNPs. The lipase can catalyze the hydrolysis of Tween 20 and cause the formation AuNPs to prevent the
of unstable Tween 20-modified AuNPs. Thus, the resultant aggregation and red-to-blue color changeof
aggregation of AuNPs. The lipase can catalyze the hydrolysis of Tween 20 and cause the formation
unstablethe
exhibited Tween 20-modified
presence of lipaseAuNPs.
[75]. Thus, the resultant aggregation and red-to-blue color change
exhibited the presence of lipase [75].
Figure 6. The schematic representation of the measurement of dipeptidyl peptidase-IV(DPP-IV) activity.

Figure
DPP-IV6. hydrolyzes
The schematic representation
its substrate, whichofabolishes
the measurement of stabilization,
electrosteric dipeptidyl peptidase-IV(DPP-IV)
which destabilizes the
activity. DPP-IVsystem
AuNP sensing hydrolyzes its AuNPs
and causes substrate, which Reproduced
aggregation. abolishes electrosteric stabilization,
with permission which
from Reference [73].
destabilizes
MDPI, 2018.the AuNP sensing system and causes AuNPs aggregation. Reproduced with permission
from Reference [73]. MDPI, 2018.
2.2. Label-Free Detection Methods
2.2. Label-Free Detection Methods
The aggregation of functionalized AuNPs can be triggered by the loss of steric or electrosteric
stabilization or by the
The aggregation gain of the stacking
of functionalized AuNPsinteraction. Unlikebythe
can be triggered thelabel-based detection
loss of steric methods,
or electrosteric
the label-free
stabilization colorimetric
or by the gain ofmethods are mostly
the stacking regulated
interaction. Unlikebytheelectrostatic
label-basedstabilization. In the the
detection methods, case
of electrostatic stabilization, a repulsive electric layer can be generated from
label-free colorimetric methods are mostly regulated by electrostatic stabilization. In the case of the surface charges
of AuNPs to
electrostatic stabilize colloids.
stabilization, a repulsiveThus,electric
the neutralization
layer can beofgenerated
surface charges,
from theinsurface
this case, resultsofin
charges
the formation
AuNPs of unstable
to stabilize colloids. AuNPs,
Thus, the which promotes of
neutralization aggregation and a in
surface charges, red-to-purple color in
this case, results change.
the
The analyte-triggered aggregation for chemical and biological sensing applications
formation of unstable AuNPs, which promotes aggregation and a red-to-purple color change. The is performed based
on the affinity of aggregation
analyte-triggered analytes suchfor as chemical
the electrostatic or hydrogen-bonding
and biological interaction
sensing applications is toward
performedunmodified
based
onAuNPs. For example,
the affinity Ma etsuch
of analytes al. devised
as the aelectrostatic
simple assayorfor the sensitive and selective
hydrogen-bonding interactioncolorimetric
toward
detection of
unmodified heparinFor
AuNPs. [76]. In the absence
example, Ma et al.ofdevised
heparin,a the poly(diallyldimethylammonium
simple chloride)
assay for the sensitive and selective
(PDDA) with
colorimetric positiveofcharges
detection heparincan easily
[76]. adsorb
In the ontoofthe
absence citrate-capped
heparin, AuNP surfaces by electrostatic
the poly(diallyldimethylammonium
attraction
chloride) (Figure
(PDDA) 7). positive
with This behavior
chargesleads to theadsorb
can easily aggregation
onto theofcitrate-capped
the AuNPs and AuNPa corresponding
surfaces by
electrostatic attraction (Figure 7). This behavior leads to the aggregation of the AuNPswhich
red-to-blue color change. On the other hand, heparin bears a high negative charge density, and can
a
strongly bindred-to-blue
corresponding PDDA via an electrostatic
color change. On interaction
the othertohand,
form heparin
a stable complex.
bears a highTherefore,
negative the PDDA
charge
inducedwhich
density, aggregation of AuNPs
can strongly bindcould
PDDA be via
effectively inhibitedinteraction
an electrostatic by heparin.to form a stable complex.
Therefore, the PDDA induced aggregation of AuNPs could be effectively inhibited by heparin.
Nanomaterials
Nanomaterials 9, x9,FOR
2019,
2019, 861 PEER REVIEW 8 of8 24
of 24
Figure 7. The schematic illustration of heparin detection using a label-free colorimetric method.
Figure
After7.the
Theaddition
schematic illustration of heparin detection using
of poly(diallyldimethylammonium a label-free
chloride) (PDDAs),colorimetric method. After
AuNPs aggregate due to
theattractive
additionelectrostatic
of poly(diallyldimethylammonium
interactions between the PDDA and the AuNPs. However, whendue
chloride) (PDDAs), AuNPs aggregate to
heparin
attractive electrostatic interactions between the PDDA and the AuNPs. However, when
is present, the PDDA molecules will interact with the heparin, which prevents the PDDA-induced heparin is
present, the PDDA
aggregation of themolecules
AuNPs. will interact with
Reproduced with the heparin, from
permission whichReference
prevents[76].
the PDDA-induced
Royal Society of
aggregation of
Chemistry, 2019. the AuNPs. Reproduced with permission from Reference [76]. Royal Society of
Chemistry, 2019.
Among various label-free colorimetric detection methods, the combination of aptamers
Among
with various AuNPs
unmodified label-free colorimetric
have been popular detectionfor methods,
many analytesthe combination
due to theofease aptamers with
of detection.
unmodified
Generally,AuNPs have been
the negatively popular
charged for many
aptamers analytes
are adsorbed dueonto
to the ease
the of detection.
surface of AuNPs Generally, the
via the DNA
negatively charged aptamers are adsorbed onto the surface of AuNPs
nitrogen bases, which leads to well-dispersed, negatively charged, aptamer-capped AuNPs in thevia the DNA nitrogen bases,
which
medialeads to well-dispersed,
of moderately negatively
high ionic strength. charged,
However, theaptamer-capped AuNPs in the
target triggered configuration swiftmedia
withinofthe
moderately high ionic strength. However, the target triggered configuration
aptamer results in the detachment of the aptamer from the AuNP surface by decreasing the aptamer swift within the aptamer
results in the
affinity detachment
to AuNPs. As aofresult,
the aptamer
the degreefromof the AuNPaggregation
AuNP surface by decreasing the aptamer
is a direct reflection affinity
of the target
to concentration
AuNPs. As a result,
and canthe degree of AuNP
be observed by aggregation is a direct reflection
the red to purple-blue of the in
color change target
the concentration
AuNP solution.
and can be
Based on observed
the similar bystrategies,
the red tothe purple-blue
label-free color change detection
colorimetric in the AuNP solution.
of various Basedincluding
targets, on the
similar strategies, the label-free colorimetric detection of various targets, including
proteins [77–80], small organic molecules [81–83], and ions, such as silver (I) [84], cadmium (II) [85] proteins [77–80],
small
andorganic
potassiummolecules
(I) [86],[81–83],
has beenand ions, such
explored as silver (I) [84], cadmium (II) [85] and potassium (I)
extensively.
[86], has been explored extensively.
These colorimetric approaches are simple and do not require the surface modification of the
These but
AuNPs, colorimetric approaches
their sensitivity areunsatisfactory.
is still simple and doTonot require the
overcome this surface
drawback, modification
we developed of thean
AuNPs,
amplified aptamer detection method by the combination of catalytic hairpin assembly (CHA)an
but their sensitivity is still unsatisfactory. To overcome this drawback, we developed and
amplified
unmodifiedaptamer
AuNPs detection
[62]. A method
dominant bymerit
the combination
of CHA overof catalytic
other hairpin assembly
amplification approaches, (CHA)
such and
as the
unmodified
polymerase AuNPs
chain [62]. A dominant
reaction (PCR), ismerit
that it ofallows
CHA over other amplification
for specific non-enzymatic approaches, such as
self-assembly the
at room
polymerase chain reaction (PCR), is that it allows for specific non-enzymatic
temperature. Unlike PCR, the current form of CHA also offers linear reaction kinetics. We recently self-assembly at room
temperature. Unlike PCR,
reported a nonlinear DNA theself-assembly
current form system of CHAthat alsoprovides
offers linear reaction
a higher kinetics. We
amplification recently
efficiency and
reported a nonlinear
more rapid DNA self-assembly
amplification kinetics [87]. A system that provides
programmed a higher
dendritic DNAamplification
nanostructureefficiency and
was generated
more rapid
using twoamplification
double-stranded kinetics [87]. Aand
substrates programmed dendritic helpers
two single-stranded DNA nanostructure
as DNA assembly was generated
components
using two double-stranded
by a target-induced substrates
cascade reaction. Then,andthis two single-stranded
nanostructure helpers by
was captured asDNA
DNA assembly
probe-capping
components
AuNPs. The release of the DNA probes from AuNPs led to the aggregation of AuNPsby
by a target-induced cascade reaction. Then, this nanostructure was captured DNA 8).
(Figure
probe-capping AuNPs. The release of the DNA probes from AuNPs led to the
By using this method, a concentration as low as 3.7 fmol of vascular endothelial growth factor (VEGF), aggregation of AuNPs
(Figure
which8).wasBymuch
usinglower
this method,
than thata of concentration
other aptamer as sensors,
low as 3.7 fmolbeofdetected
could vascularwithin
endothelial
an hour. growth
factor (VEGF), which was much lower than that of other aptamer sensors, could be detected within
an hour.
Nanomaterials2019,
Nanomaterials 2019,9,9,x861
FOR PEER REVIEW 99of
of24
24
Figure 8. The schematic illustration of target-induced branched DNA cascade reaction and sensing
using unmodified AuNPs. Reproduced with permission from Reference [87]. Elsevier B.V., 2016.
Figure 8. The schematic illustration of target-induced branched DNA cascade reaction and sensing
using unmodified
3. Etching-Based AuNPs. Reproduced
Colorimetric Detection with permission from Reference [87]. Elsevier B.V., 2016.
Presently, various
3. Etching-Based AuNPs,
Colorimetric such as gold nanospheres, gold nanorods (AuNRs) [88,89], gold
Detection
nanotriangles, and gold nanourchins [88] have been used as etching-based colorimetric sensors.
Presently,
Generally, variousprocess
the etching AuNPs, sucha as
causes goldinnanospheres,
change goldofnanorods
the shape or size (AuNRs)
the nanoparticles and[88,89], golda
therewith
nanotriangles, and gold nanourchins [88] have been used as etching-based
shift in the LSPR extinction peak and a subsequent change in color. For example, AuNRs have two colorimetric sensors.
Generally,
separate SPR the etching
absorptionprocess
peakscauses a change
defined in the shape
as a transverse andor asize of the nanoparticles
longitudinal and therewith
mode, respectively [90].
aThe
shift in the LSPR extinction peak and a subsequent change in color. For example,
longitudinal surface plasmon of AuNRs is strongly dependent on the aspect ratio of the nanorods. AuNRs have two
separate SPR absorption
As the aspect peaksthe
ratio decreases, defined as a transverse
longitudinal peak of theandAuNRs
a longitudinal
shows amode, respectively
characteristic blue [90].
shift.
The longitudinal surface plasmon of AuNRs is strongly dependent on the
Therefore, different optical properties can be obtained by properly tuning the aspect ratio to changeaspect ratio of the
the
nanorods. As the aspect ratio decreases, the longitudinal peak of the AuNRs
wavelength range of the optical properties of the AuNRs. Based on these shape-induced anisotropic shows a characteristic
blue shift.
optical Therefore,
properties, different
AuNRs areoptical properties
more ideal can be obtainedfor
gold nanostructures byetching-based
properly tuning the aspect
sensing ratio
strategies,
to change
and becausethe their
wavelength
tips haverange of the
a high optical
surface properties
energy, of the AuNRs.
the etching reaction Based
occurson these
easily atshape-induced
the AuNR tips.
anisotropic optical properties, AuNRs − are more ideal gold nanostructures
The use of etchants like H2 O2 and I ions can preferentially etch the terminal ends of AuNRs,for etching-based sensing
which
strategies, and because their tips have a high surface energy, the etching reaction
leads to a lower aspect ratio or spherical AuNPs. Moreover, an obvious blue shift in the longitudinal occurs easily at the
AuNR
mode of tips.
theThe
SPRusepeak ofand
etchants like H2O
color change 2 and I ions can preferentially etch the terminal ends of
from
−
green to red will be observed.
AuNRs, which leads to a lower aspect ratio or spherical AuNPs. Moreover, an obvious blue shift in
3.1.longitudinal
the H2 O2 -Mediatedmode Etching
of theReactions
SPR peak and color change from green to red will be observed.
Although the etching of AuNRs by H2 O2 has been reported [91], there are several drawbacks in the
3.1. H2O2-Mediated Etching Reactions
reaction conditions, such as the high H2 O2 concentrations, high temperature, and acidic environments,
Although
thereby limiting thethe
etching of AuNRs
applicability by Hsystem
of this 2O2 hasfor
been reported
sensing [91], there
purposes. are several
However, drawbacks in
the introduction of
the reaction
catalytic speciesconditions, such ions
such as metal as theandhigh H2O2 could
enzymes concentrations,
overcome this highissue
temperature,
[92]. Zhang and acidic
et al. [93]
environments,
developed a Cothereby2+ sensor limiting
based ontheFenton-like
applicability of this system for
reaction-mediated sensing
etching purposes.
of AuNRs. InHowever, the
this approach,
2+
introduction ofthe
catalytic species suchof Has
Co induced decomposition 2 Ometal ions and
2 to generate enzymesradicals
hydroxyl could overcome
and these this issueetched
radicals [92].
Zhang
the AuNRset al. [93] developed
in the presencea of CoSCN − and
2+ sensor based on Fenton-like
the AuNRs underwent reaction-mediated etching
a shape conversion of AuNRs.
from rods to
In this approach,
spheres Co2+ induced
with an obvious color the decomposition
change from greenoftoHred. 2O2 to generate
Under hydroxyl
optimized radicals and
conditions, this these
assay
radicals etched detect
could visually the AuNRs 2+
Co in thenM
at 40 presence
withinof SCN Due
7 min. − and totheitsAuNRs underwent
good sensing a shape conversion
performance in terms of
from rods toselectivity,
sensitivity, spheres withand an obvioustime,
detection colorthis
change
method fromhasgreen to red. Under
the potential for theoptimized conditions,
on-site monitoring of
this 2+
Co assay could visually
. In another detect
recent study Co at 40bynM
2+
conducted Wengwithin
et al.7[94],
min.cetyltrimethylammonium
Due to its good sensing performance
bromide (CTAB) in
terms
was foundof sensitivity,
to accelerate selectivity,
the rate ofand
the detection time,reaction
H2 O2 etching this method has the of
in the presence Cu2+ . The
potential for longitudinal
the on-site
monitoring of Co 2+. In another recent study conducted by Weng et al. [94], cetyltrimethylammonium
SPR band of the AuNRs shifted gradually to longer wavelengths as the concentration of CTAB increased
bromide
from 1 to(CTAB)
40 mM.was found to accelerate the rate of the H2O2 etching reaction in the presence of Cu2+.
The longitudinal
Except for using SPR band
metal ionsof
as athe AuNRs
catalytic shifted
medium, gradually
enzymes could to longer wavelengths
remarkably as the
enhance the efficiency
concentration of CTAB increased from 1 to 40 mM.
of the etching reaction with fast reaction kinetics. Saa et al. [95] reported that the H2 O2 -triggered
Except for using metal ions as a catalytic medium, enzymes could remarkably enhance the
efficiency
etching of of AuNRs
the etching
causedreaction with fastchange
a considerable reaction kinetics.
in the Saa etpink,
color from al. [95]
bluereported
to yellow,that
as athe H2O2- of
function
triggered
glucoseetching of AuNRs
concentration causedhorseradish
by using a considerable change (HRP).
peroxidase in the color from pink,this
Consequently, bluemethod
to yellow,hadashigh
a
function of glucose concentration by using horseradish peroxidase (HRP). Consequently,
sensitivity with a detection limit of 10 µM in a 15 min detection time. Saa et al. [96] also designed an this method
had high sensitivity
ultrasensitive with a detection
colorimetric sensor forlimit of 10 μM in
the enzymatic a 15 min
activity detection time. Saa(AChE)
of acetylcholinesterase et al. [96] alsoon
based
designed
protectinganthe ultrasensitive
AuNRs against colorimetric
enzymaticsensor
etchingfor by the
using enzymatic activityThe
thiol molecules. of absence
acetylcholinesterase
of AChE made
(AChE) based on protecting the AuNRs against enzymatic etching by
the shortening of AuNRs by the HRP-accelerated oxidative etching. However, with the addition using thiol molecules. The of
absence of AChE
the AChE, made the shortening
acetylthiocholine (ATCh)of inAuNRs by thewas
the solution HRP-accelerated
hydrolyzed byoxidative
AChE to etching.
produceHowever,
thiocholine.
with the addition of the AChE, acetylthiocholine (ATCh) in the solution
Thiocholine molecules then bound to the tips of the AuNRs, which led to a higher surface was hydrolyzed by AChE to
coverage
produce
of thiol molecules at the terminal end of the AuNRs. This reaction gradually decreased the ratea of
thiocholine. Thiocholine molecules then bound to the tips of the AuNRs, which led to
higher surfaceoxidation
anisotropic coverageofofAuNRs
thiol molecules
by HRP as at the
the AChE
terminal end of the AuNRs.
concentration increased, This reaction gradually
accompanied by a color
decreased the rate of anisotropic oxidation of AuNRs by HRP as the AChE
change from blue to brown. The resulting LOD was 0.04 mU/mL which is lower than that of other concentration increased,
accompanied by a color
currently reported change
AChE fromThe
sensors. blueauthors
to brown.
alsoThe resulting LOD
demonstrated was 0.04 mU/mL
the detection of AChEwhich is
inhibitors
lower
suchthan that of and
as paraoxon othergalanthamine
currently reported AChE concentrations
in nanomolar sensors. The authors using thisalsostrategy.
demonstrated
Lu et al.the[97]
detection of AChE inhibitors such as paraoxon and galanthamine in nanomolar concentrations
developed the visual detection of catalase based on the inhibition of a H2 O2 -mediated etching reaction using
this strategy.
(Figure 9). Lu et al.
In the [97] developed
absence the visual
of the catalase, the detection
etching ofofAuNRscatalaseoccurred
based onand the spherical
inhibitionAuNPs
of a H2O 2-
were
mediated etching reaction (Figure 9). In the absence of the catalase, the etching
obtained. Under these conditions, the solution had a pink color. In the presence of the enzyme, of AuNRs occurred
andthespherical AuNPsof
decomposition were
H2 Oobtained. Under these conditions, the solution had a pink color. In the
2 to H2 O and O2 was catalyzed, which slowed down the etching kinetics
presence of theinenzyme,
and resulted the AuNR theshape
decomposition
remaining of H2Ounchanged.
nearly 2 to H2O and O2 assay
This was catalyzed, which sensitivity
showed a better slowed
down the etching kinetics and resulted in the AuNR shape remaining nearly unchanged.
to the detection of catalase than other sensors, and it was also used in a lab-based test that simulates This assay
showed a better sensitivity
real test conditions. to the detection of catalase than other sensors, and it was also used in a
lab-based test that simulates real test conditions.
Figure
Figure 9. The
9. The schematic
schematic illustration
illustration forfor colorimetric
colorimetric detection
detection of catalase
of catalase based
based onon
thethe decomposition
decomposition
of H O ,
of H2O22, which
2 which inhibits H O etching
inhibits H2O22 etching
2 of AuNRs. Reproduced with permission from
of AuNRs. Reproduced with permission from Reference Reference [97].
[97].
Royal Society of Chemistry,
Royal Society of Chemistry, 2016. 2016.
3.2. Ion-Mediated Etching Reactions

3.2. Ion-Mediated Etching Reactions
It has been reported that halide ions increase the oxidative etching of AuNRs efficiently because
It has been reported that halide ions increase the oxidative etching of AuNRs efficiently because
they promote the solubility of gold monoxide [98,99], particularly in iodine-mediated etching [100].
they promote the solubility of gold monoxide [98,99], particularly in iodine-mediated etching [100].
Iodine, acting as an oxidant, asymmetrically etches AuNRs in the presence of cetyltrimethylammonium
Iodine, + acting as an oxidant, asymmetrically etches AuNRs in the presence of
(CTA ) ions due to the low surface passivation at the end terminals, which leads to an AuNR shape
cetyltrimethylammonium (CTA+) ions due to the low surface passivation at the end terminals, which
conversion and color change [101–104]. For example, the sensitive visual detection of molybdate was
leads to an AuNR shape conversion and color change [101–104]. For example, the sensitive visual
reported using the iodine-mediated etching assay [105]. Although H2 O2 could oxidize I− to I2 which
detection of molybdate was reported using the iodine-mediated etching assay [105]. Although H2O2
caused the corrosion of CTAB stabilized AuNRs in the presence of a weak acid solution, the reaction
could oxidize I− to I2 which caused the corrosion of CTAB stabilized AuNRs in the presence of a weak
kinetics was very slow. The addition of molybdate, which is a peroxidase-like molecule, resulted in
acid solution, the reaction kinetics was very slow. The−addition of molybdate, which is a peroxidase-
the acceleration of the reaction between H O and I to produce large amounts of I and the effective
like molecule, resulted in the acceleration 2of 2the reaction between H2O2 and I− to2 produce large
etching of AuNRs along the longitudinal direction. Good specificity and high sensitivity with a LOD
amounts of I2 and the effective etching of AuNRs along the longitudinal direction. Good specificity
of 1 nM molybdate were all achieved. This proposed strategy was considered advantageous compared
and high sensitivity with a LOD of 1 nM molybdate were all achieved. This proposed strategy was
considered
to previous advantageous compared as
molybdate biosensors to itprevious
comprised molybdate
a simplebiosensors
design, was ascost-effective
it comprisedand a simple
did not
design,
require was cost-effective
labeling. Further,and didbasis
on the not require labeling. Further,
of this phenomenon, Zhang onetthe al.basis
[106] of this phenomenon,
reported a colorimetric
Zhang
glucoseet al. [106] based
sensor reported on athecolorimetric glucose sensor
molybdate-promoted basedofonAuNRs.
etching the molybdate-promoted
In the presence ofetching glucose,
of glucose
AuNRs.oxidase
In the presence of glucose, glucose oxidase (GOx) can catalyze
(GOx) can catalyze the oxidation of glucose to generate gluconic the oxidationacid of glucose
and Hto 2 O2 .
generate gluconic of
In the presence acid and H2O2H
molybdate, . InO
2 2
the presence
immediately of molybdate,
oxidized I H
− to 2IO,2 which
2
immediately
etched oxidized
the AuNRs I− to I2,
in the
which etched the AuNRs in the longitudinal direction. In this case, the LSPR
longitudinal direction. In this case, the LSPR peak shift was directly dependent on the concentration of peak shift was directly
dependent
glucose inon thethe concentration
sample. Under optimal of glucose in thethis
conditions, sample. Under optimal
assay exhibited a good conditions, this assay
linear relationship in the
exhibited a good linear relationship in the range from 0.3 to 1 μM with a LOD
range from 0.3 to 1 µM with a LOD of 0.1 µM. In another example, a colorimetric assay that relies on the of 0.1 μM. In another
example,
principle a colorimetric assay etching
of the I2 -mediated that relies on thehas
strategy principle of the I2-mediated
been investigated etching
for the on-site strategyofhas
detection been
dissolved
investigated
oxygen [107]. for In
thethis
on-site
study, detection
2+
Mn was of dissolved
first oxidizedoxygen
to Mn[107].and
3+ In this
Mn study,
4+ Mn acidification,
and after
2+ was first oxidized
I− was
to oxidized
Mn and to
3+ Mnform
4+ andI2after
by Mn acidification,
3+ and MnI4+was −
and oxidized
an obvious to form
color Ichange
2 by Mn 3+
from and Mnto red
blue
4+ and was
an obvious
observed
color change
(Figure 10). from blue to red was observed (Figure 10).
Figure 10. The schematic illustration for the detection of dissolved oxygen based on the iodine-mediated
Figure 10. The schematic illustration for the detection of dissolved oxygen based on the iodine-
etching of AuNRs. Reproduced with permission from Reference [107]. Royal Society of Chemistry, 2016.
mediated etching of AuNRs. Reproduced with permission from Reference [107]. Royal Society of
Chemistry, 2016. 2+
In addition to halide ions, Cu was found to promote significant AuNR etching by dissolved
oxygen, which has a strong affinity for the Au surface atoms to form the stable Au–O complex [108].
In addition to halide ions, Cu2+ was found to promote significant AuNR etching by dissolved
The addition of Cu2+ helped etch the Au–O complex on the AuNR surface, and promoted electron
oxygen, which has a strong affinity for the Au surface atoms to form the stable Au–O complex [108].
transfer from Au to O. At Cu2+ concentrations lower than 1 mM, the end-cap reshaping conditions were
The addition of Cu2+ helped etch the Au–O complex on the AuNR surface, and promoted electron
satisfied, a slight etching reaction proceeded and the AuNRs quickly underwent a shape transformation.
transfer from Au to O. At Cu2+ concentrations lower than 1 mM, the end-cap reshaping conditions
At higher concentrations of Cu2+ , a variation in the end-cap shape distribution and an increase in
were satisfied, a slight etching reaction proceeded and the AuNRs quickly underwent a shape
the anisotropic etching of AuNRs were observed. Later, similar observations were also reported
transformation. At higher concentrations of Cu2+, a variation in the end-cap shape distribution and
by Alex et al. [109], who studied the colorimetric detection of Cr6+ by Cr6+ -assisted etching and
an increase in the anisotropic etching of AuNRs were observed. Later, similar observations were also
reshaping of dumbbell-shaped AuNRs. The LOD of this strategy was 71 nM, which is lower than
reported by Alex et al. [109], who studied the colorimetric detection of Cr6+ by Cr6+-assisted etching
that of other colorimetric methods and comparable to the results obtained from fluorescence methods.
and reshaping of dumbbell-shaped AuNRs. The LOD of this strategy was 71 nM, which is lower than
Zhang et al. [110] developed a rapid, visual method to detect Cu2+ based on the catalytic etching
that of other colorimetric methods and comparable to the results2+obtained from fluorescence
of AuNRs. In the presence of CTAB, AuNRs were oxidized by Cu to produce AuBr2 –CTA+ and
methods. Zhang + et al. [110] developed a rapid, visual method
+ to detect Cu2+ based on the catalytic
CuBr2 -CTA complexes and thereafter the CuBr2 -CTA complex as an2+ ion-association agent was
etching of AuNRs. In the presence of CTAB, AuNRs were oxidized by Cu to produce AuBr2–CTA+
reduced by dissolved oxygen to produce Cu2+ . Thus, there was no Cu2+ consumption in the etching
and CuBr2-CTA complexes and thereafter the CuBr2-CTA complex as an ion-association agent was
+ +
process, which led to the maximal etching of the AuNRs. The system showed a significant improvement
reduced by dissolved oxygen to produce Cu2+. Thus, there was no Cu2+ consumption in the etching
for practical applications in real samples like the sea and digested shellfish samples due to its good
process, which led to the maximal etching of the AuNRs. The system showed a significant
selectivity and high tolerance to the high salinity of these complex matrices.
improvement for practical applications in real samples like the sea and digested shellfish samples
Additionally, Pd2+ have been reported to increase the etching rate of gold nanomaterials [111–113]
due to its good selectivity and high tolerance to the high salinity of these complex matrices.
but there are some drawbacks such as long reaction time, low sensitivity, and complicated process.
Additionally, Pd2+ have been reported to increase the etching rate of gold nanomaterials [111–
Recently, Lan et al. [114] proposed a simple and fast Pd2+ sensor in complex real samples. They used
113] but there are some drawbacks such as long reaction time, low sensitivity, and complicated
S2 O3 2− absorbed on the gold surface to induce a redox reaction2+at the solid–liquid interface due to
process. Recently, Lan et al. [114] proposed a2−simple and fast Pd sensor in complex real samples.
the electrostatic interactions between S2 O3 and the CTAB-capped AuNRs. This, in turn, induced
They used S2O32− absorbed on the3−gold surface to induce a redox reaction at the solid–liquid interface
the formation of an Au(S2 O3 )2 complex, which 2−slowly dissolved the AuNRs. The etching rate was
due to the electrostatic interactions between S2O3 and the CTAB-capped AuNRs. This, in turn,
accelerated by adding Pd2+ because the quick formation of the Pb-Au alloy (AuPb2 and AuPb3 ) caused
induced the formation of an Au(S2O3)2 complex, which slowly dissolved the AuNRs. The etching rate
3−
a significant reduction in the standard electron potential of gold in AuNRs and, therefore enhances the
was accelerated by adding Pd2+ because the quick formation of the Pb-Au alloy (AuPb2 and AuPb3)
caused a significant reduction in the standard electron potential of gold in AuNRs and, therefore
enhances the dissolution rate of the AuNRs. Under optimal conditions, this probe was highly
sensitive (LODrate
dissolution = 4.3
ofnM) and selective
the AuNRs. Undertoward Pb2+conditions,
optimal ions withinthis
a rapid detection
probe timesensitive
was highly (10 min).(LOD =
4.3 nM) and selective toward Pb2+ ions within a rapid detection time (10 min).
4. Growth-Based Colorimetric Sensing Strategies
4. The
Growth-Based
growth of Colorimetric SensingonStrategies
small-sized AuNPs catalytic seeds such as Au3+ and Ag+ by enzymatic or
chemical transformation
The is a new trend
growth of small-sized in designing
AuNPs a biological
on catalytic andaschemical
seeds such Ag+ by enzymatic
colorimetric
Au3+ and sensing
strategy.
or chemical transformation is a new trend in designing a biological and chemical colorimetric
sensing strategy.
4.1. Non-Enzyme-Mediated Growth Reactions
4.1. Non-Enzyme-Mediated Growth Reactions
It is well-known that H2O2 can be used as the reductant for AuNP growth [115] or as the catalyst
for the Itmetallization
is well-known ofthat
AuNPs
H2 O2[116].
can beBased
used asonthe
these principles,
reductant for AuNPa colorimetric
growth [115] assay
or asfor
themetal
catalystionfor
detection was designed
the metallization [117].[116].
of AuNPs In theBased
absence of theprinciples,
on these target Hga colorimetric
2+ ions, the decomposition
assay for metal ofion
H2O 2 was
detection
catalyzed by gold
was designed nanoclusters
[117]. (AuNCs)
In the absence of theand theHg
target Au2+crystal growth
ions, the kinetics were
decomposition of Hslow,
O
2 2 which
was led
catalyzed toby
thegold
formation of crystals with an ill-defined morphology, including aggregated
nanoclusters (AuNCs) and the Au crystal growth kinetics were slow, which led to the formation AuNPs. However,
theofaddition of target
crystals with Hg2+ ionsmorphology,
an ill-defined inhibited theincluding
catalytic aggregated
ability of the AuNCs
AuNPs. toward the
However, H2Oaddition
2 so the of
reduction
target Hg 2+
of Auions3+ with H2O2the
inhibited occurs at aability
catalytic fast rate,
of theand non-aggregated
AuNCs toward H2 OAuNPs so the were of Au3+
produced.
reduction
2
Hydroxylamine
with H2 O2 occurs (NH at2OH)
a fast is another
rate, reductant which
and non-aggregated AuNPscouldwerethermodynamically
produced. Hydroxylaminereduce Au (NH 3+ to
2 OH)
AuNP, and Hg
is another 2+ favorably
reductant absorbed
which could on the Au surface to form
thermodynamically reduce a solid3+
Au amalgam-like
to AuNP, and 2+
structure. Thus,
Hg favorably
Zhao et al. [118]
absorbed on the combined
Au surfacethese two phenomena
to form for the development
a solid amalgam-like of a Hg
structure. Thus, 2+ sensor.
Zhao In this
et al. [118] case,
combined
thethese
growth twoofphenomena
small-size AuNPs
for the could be controlled
development of a Hg 2+
by the amount
sensor. In of adsorbed
this case, theHg 2+ on the
growth of AuNPs,
small-size
and thus give
AuNPs couldrisebetocontrolled
Au nanostructures
by the amount of different
of adsorbed Hg2+
sizes and solutions of different
on the AuNPs, andcolors
thus give(Figure
rise 11).
to Au
The major feature of both studies is the direct colorimetric detection of Hg 2+ without any ligand
nanostructures of different sizes and solutions of different colors (Figure 11). The major feature of both
studies is the direct colorimetric detection of Hg2+ without any ligand labeling.
labeling.
Figure 11.11.
Figure TheThe
schematic illustration
schematic of the
illustration amount
of the amountof of
HgHgon on
thethe
surface of of
surface AuNP-controlled thethe
AuNP-controlled
growth of of
growth AuNPs. Reproduced
AuNPs. Reproduced with permission
with from
permission Reference
from [118].
Reference Elsevier
[118]. B.V.,
Elsevier 2017.
B.V., 2017.
Researchers
Researchers havehave also
also explored
explored different
different sensing
sensing methods
methods forfor proteins
proteins and and small
small molecules
molecules in in
additiontotometal
addition metal ionion detection.
detection.Shen
Shenet al.
et [119] developed
al. [119] a rapida colorimetric
developed detectiondetection
rapid colorimetric of tetracycline
of
broad-spectrum antibiotics based on the direct reduction of Au 3+ into AuNPs without added AuNP
tetracycline broad-spectrum antibiotics based on the direct reduction of Au into AuNPs without 3+
seeds.
added Tetracycline
AuNP antibiotics enable
seeds. Tetracycline the reduction
antibiotics Au3+ to atomic
enable theofreduction of Au3+Au, which Au,
to atomic could formcould
which AuNPs
spontaneously, with the oxidation of the phenol group on the benzene ring.
form AuNPs spontaneously, with the oxidation of the phenol group on the benzene ring. As the As the concentrations
of tetracycline
concentrations of increased,
tetracyclinethe SPR peaks
increased, the ofSPRthepeaks
AuNPs were
of the intensified
AuNPs and slightly
were intensified andblue-shifted.
slightly
Although they
blue-shifted. provided
Although theyaprovided
fast method formethod
a fast tetracycline antibiotics,antibiotics,
for tetracycline this assay this
could not could
assay distinguish
not
between different families of tetracycline. Li et al. [120] investigated the effect of AuNP
distinguish between different families of tetracycline. Li et al. [120] investigated the effect of AuNP particle sizes
particle sizes on their performance as colorimetric lysozyme probes. They found that the smaller size of
on their performance as colorimetric lysozyme probes. They found that the smaller size (15 nm)
(15AuNPs
nm) ofcan be aggregated
AuNPs by the addition
can be aggregated of lysozyme
by the addition due to the
of lysozyme Au–NH
due bonds but
to the2Au–NH the sensitivity
2 bonds but the
was unsatisfactory. Thus, a growth-based colorimetric method was performed to improve the sensing
performance of this assay by using NH2 OH as a reductant, which showed a good sensitivity with a
LOD of 0.1 nM.
Recently, DNA molecules have been reported to affect the diffusion of Au3+ to the seed and
control the morphology of AuNPs [121,122]. Some researchers have combined DNA aptamers with
colorimetric diagnostics using the DNA-mediated growth system. Soh et al. [123] described a detection
method for ochratoxin A (OTA) by using aptamer-controlled AuNP growth. The as-prepared AuNPs
were capped with DNA aptamers through physical adsorption and the amount of aptamer strands were
controlled by the specific aptamer–target interaction depending on the target concentration; the lower
the OTA concentration, the higher the amount of capped aptamer. Hence, AuNPs with high aptamer
coverage exhibited a branched morphology and blue solutions, whereas those with low aptamer
coverage had a smooth, spherical morphology and red solutions. The result could be observed visibly
by a change in the color of the solution from red to blue and quantified via absorbance spectroscopy.
Likewise, Zhu et al. [124] employed this aptamer-mediated control of AuNPs morphology for the
naked-eye detection of cholic acid.
4.2. Enzyme-Mediated Growth Reactions

It has been demonstrated that the reduction of Au3+ to AuNPs or the deposition of metals on AuNP
seeds can be catalyzed by enzymes. For example, Liu et al. [125] reported a GOx-mediated nanocrystal
growth for the attomolar detection of prostate-specific antigen (PSA). Here, secondary antibody
(Ab2)–GOx conjugate functionalized magnetic beads were used as a capture probe, and primary
antibodies (Ab1) were used as a detection probe for the specific recognition of PSA. Because solutions
of small-sized AuNPs in low concentrations (<10 nM) are generally almost colorless, the change in
size from 5 nm to larger sizes (>10 nm) can cause an obvious color change from colorless to red.
Therefore, after the formation of immunocomplex (Ab1–PSA–Ab2-GOx), GOx triggered the oxidation
of glucose to produce H2 O2 , which resulted in the enlargement of 5 nm AuNPs and the obvious color
change from colorless to red. This assay showed a LOD of 93 aM, which is more than four orders of
magnitude higher than that of the commercial ELISA method.
An enzymatic silver deposition assay based on the reaction between a certain enzyme, AuNPs
and Ag+ to generate a color change has been extensively used for different applications [126–128].
Gao et al. [126] developed a high-resolution colorimetric assay for monitoring alkaline phosphatase
(ALP) activity using enzyme-guided in situ formation of a silver shell on AuNRs (Figure 12). In this
approach, the LSPR of AuNRs was tuned by the ALP-assisted crystal growth to favor the formation of
a Ag+ coating around the AuNRs, which was accompanied with a perceptible color change from red,
orange, yellow, green, cyan, blue and to violet with a high resolution. ALP produced ascorbic acid by
hydrolyzing ascorbic acid 2-phosphate, which subsequently reduced the Ag+ to metallic silver on the
surface of AuNR. The color change and the shift in the SPR peak were proportional to the size of the
silver nanoshell, which indirectly depended on the ALP activity. They experimentally demonstrated
the significant ability of the metallization of the AuNRs to detect the enzyme activity of ALP down
to 14.5 mU/mL in serum. In other studies, similar concepts but using different shapes (sphere [129],
rod [130], star [131], and bipyramid [132]) of gold nanomaterials have been reported for the detection
of protein targets.
Figure 12. The schematic illustration of the colorimetric sensing of phosphatase activity based
Figure 12. The schematic illustration of the colorimetric sensing of phosphatase activity based on
on enzymatic reaction-aided silver deposition onto AuNR to generate different color changes.
enzymatic reaction-aided silver deposition onto AuNR to generate different color changes.
Reproduced with permission from Reference [121]. American Chemical Society, 2014.
Reproduced with permission from Reference [121]. American Chemical Society, 2014.
5. Nanoenzyme-Based Colorimetric Sensing Strategies
5. Nanoenzyme-Based Colorimetric Sensing Strategies
Recently, AuNPs with different surface modifications have been found to possess an intrinsic
Recently,
enzyme-mimetic AuNPs withwhich
activity, different surface
provides newmodifications
insights into thehave been found
catalytic to possess
application of thisan intrinsic
nanomaterial
enzyme-mimetic
in colorimetric activity,
biosensing. whichCompared
provides with new natural
insights enzymes,
into the artificial
catalytic AuNP
application
enzymes of thishave
nanomaterial in colorimetric biosensing. Compared with natural enzymes,
several advantages, such as high stability against denaturing, easy synthesis, and facile storage.artificial AuNP enzymes
have several advantages,
Therefore, applications such as high
of AuNPs asstability
artificialagainst
enzymes denaturing,
are currentlyeasyunder
synthesis, and facile storage.
investigation.
Therefore, applications of AuNPs as artificial enzymes are currently under investigation.
5.1. Peroxidase-Like Activity
5.1. Peroxidase-Like Activity
Positively- and negatively-charged AuNPs have been reported to possess intrinsic peroxidase
Positively-
activity and negatively-charged
and have been used in biochemical AuNPsanalyses
have been reportedThe
[133,134]. to possess
chargedintrinsic
AuNPsperoxidase
can catalyze
activity and haveofbeen
the oxidation used in
substrate biochemical analyses [133,134].
3,3,5,5-tetramethylbenzidine (TMB)Theincharged AuNPs
the presence ofcan
H2 O catalyze the
2 to generate
oxidation of substrate
a blue color 3,3,5,5-tetramethylbenzidine
in aqueous solutions. Thus, monitoring (TMB) the in the presence
color changeofof H2TMB
O2 to could
generate a bluean
provide
color in aqueous
indirect methodsolutions.
to fabricateThus, monitoring
colorimetric the color
assays change of For
for substrates. TMB could provide
example, Jiang etan al. indirect
prepared
method to fabricate colorimetric
chitosan-functionalized assays for substrates.
(positively-charged) AuNPs For which example,
exhibitedJiang et al.
better prepared chitosan-
peroxidase-like activity
functionalized (positively-charged)
than that exhibited by natural enzymesAuNPs[135].
which exhibited better
Additionally, peroxidase-like
glucose was detectedactivity thansystem
in a buffer that
exhibited
with a LOD by natural
of 3 mM enzymes
and in [135].
60%Additionally,
serum with aglucoseLOD of was12 detected
mM. In ainfurther
a bufferstudy,
system with
they a
found
LODthatofHg 2+
3 mMcould
and insignificantly
60% serum with enhancea LODtheofcatalytic
12 mM. ability
In a further study, they found that AuNPs
of chitosan-functionalized Hg could
2+ [136],
significantly enhance
and constructed anthe catalytic
assay for Hg 2+ detection.
ability The Hg2+ detection
of chitosan-functionalized AuNPs [136],had
method and aconstructed
linear range an of
assay for Hg
0.04–10.2 nM2+ detection. The Hg
with a detection 2+ detection
limit of 20 nM.method
Wu et al.had a linear range
synthesized of 0.04–10.2 (DAP)-capped
2,6-diaminopurine nM with a
detection
AuNPs limitwhichofexhibited
20 nM. peroxidase-like
Wu et al. synthesizedactivity 2,6-diaminopurine
[137]. The activity of (DAP)-capped
DAP–AuNPs AuNPs which
can be improved
by Fe2+peroxidase-like
exhibited activity [137].
. The hydroxyl radicals mightThe activity ofeffectively
be produced DAP–AuNPs by the cancomplex
be improved by Fe2+. The
of DAP–AuNPs and
2+
hydroxyl
Fe , whichradicals
ledmight
to thebe produced effectively
enhancement by the activity.
of the catalytic complexTherefore,
of DAP–AuNPs and Fe
a sensitive 2+
Fe , which
2+ sensorled was
to reported
the enhancement
with a LOD of the catalytic
as low as 1.28activity. Therefore,
nM. Because a sensitive
hemoglobin (HB)Fe 2+ sensor
with Fe2+ in red
wastoreported
O2 binds with a
blood
LOD as(RBC),
cells low asthis
1.28 nM.
assayBecause hemoglobin
was applied (HB) withofOHB
for the detection 2 binds
and to Fe2+in
RBCs inurine
red blood cells (RBC), this
samples.
assay was applied
Notably, thefor the detection of
peroxidase-like HB andactivity
catalytic RBCs in is urine
affected samples.
by the surface properties of the AuNPs
and the particle-mediated electron transfer processes. The positively-charged AuNPs have superior
peroxidase-like activities compared to the negatively-charged AuNPs. However, several molecules
can be used for promoting activities of negatively-charged AuNPs. Therefore, on the basis of their
effects on the activities of negatively-charged AuNPs, several targets have been detected. Shah et al.
reported that adenosine triphosphate (ATP) could significantly improve the peroxidase-like activity of
citrate-capped AuNPs [138], and developed an assay for detecting ATP (Figure 13). By contrast, many
groups found that the absorption of DNA aptamers on AuNPs inhibited the activities of citrate-capped
AuNPs [139,140]. Like a competitive inhibition approach, the presence of the target could allow the
aptamer to detach from the AuNP surfaces in a target concentration-dependent manner, which resulted
in the reactivation of the peroxidase-like activity of the AuNPs. Likewise, the catalytic activity could
be modified by the amount of cysteine [141]. However, the optimal catalytic activity of AuNPs was in
acidic conditions
Nanomaterials (around
2019, 9, x FOR pH 4), which restricts their practical applications.
PEER REVIEW 15 of 24
Figure13.
Figure The schematic
13. The schematicillustration of the
illustration of colorimetric sensingsensing
the colorimetric mechanism for adenosine
mechanism triphosphate
for adenosine
(ATP) based on the ATP-promoted nanozyme activity of AuNPs. Reproduced
triphosphate (ATP) based on the ATP-promoted nanozyme activity of AuNPs. Reproduced withwith permission from
Reference [138]. Elsevier B.V., 2015.
permission from Reference [138]. Elsevier B.V., 2015.
5.2. Other Enzyme-Like Activity
Notably, the peroxidase-like catalytic activity is affected by the surface properties of the AuNPs
and theInparticle-mediated
addition to the peroxidase-like
electron transfer activity, AuNPs
processes. The have also been demonstrated
positively-charged AuNPs have to have other
superior
enzyme-mimicking
peroxidase-like activities
activities for colorimetric
compared assay applications
to the negatively-charged such asHowever,
AuNPs. glucose oxidase,
severalsuperoxidase
molecules
can be used for promoting activities of negatively-charged AuNPs. Therefore, on the basis of AuNPs
dismutase, and catalase-like activity. Zhao et al. synthesized supramolecular functionalized their
which
effects onpossessed two enzyme-like
the activities propertiesAuNPs,
of negatively-charged using cyclodextrin as both
several targets thebeen
have stabilizer and Shah
detected. the reducing
et al.
agent [142].
reported Moreover,triphosphate
that adenosine the cyclodextrin-modified AuNPs wereimprove
(ATP) could significantly rather robust for the cascadeactivity
the peroxidase-like reaction;
reactions from glucose to gluconic acid and
of citrate-capped AuNPs [138], and developed an 2assay H O 2 (glucose oxidase-mimicking activity),
for detecting ATP (Figure 13). By contrast, to H2 O
andgroups
many oxidized TMB
found (peroxidase-mimicking
that the absorption of DNAbehavior),
aptamers on were catalyzed
AuNPs by the activities
inhibited sole supramolecular
of citrate-
functionalized AuNPs. Chen et al. developed a simple colorimetric strategy for
capped AuNPs [139,140]. Like a competitive inhibition approach, the presence of the target could protein targets using
allow the aptamer to detach from the AuNP surfaces in a target concentration-dependent manner,for
aptamer–gold nanoparticle conjugates [143]. These conjugates included catalytically active AuNPs
the amplification
which resulted in theofreactivation
the colorimetric
of thereadout responseactivity
peroxidase-like and anchored aptamers
of the AuNPs. for target
Likewise, therecognition.
catalytic
In the presence of thrombin, the aptamer–thrombin interaction effectively masked
activity could be modified by the amount of cysteine [141]. However, the optimal catalytic activity the catalytic AuNP
of
surface
AuNPs andinhampered
was the access
acidic conditions of 4-nitrophenol
(around to therestricts
pH 4), which surfacestheir
of AuNPs. Without
practical thrombin, however,
applications.
yellow 4-nitrophenol could freely attach to the catalytic surface and turn to colorless 4-aminophenol.
5.2. Otheron
Based Enzyme-Like Activitythe LOD was 0.1 nM with the naked eye, which indicated an ultrahigh
this mechanism,
sensitivity assay. Similar approaches based on the conversion of 4-nitrophenol to 4-aminophenol had
In addition to the peroxidase-like activity, AuNPs have also been demonstrated to have other
been reported for the detection of other protein targets [144–146]. Last year, Taghdisi et al. developed
enzyme-mimicking activities for colorimetric assay applications such as glucose oxidase,
the amplified colorimetric aptasensor for zearalenone based on the exonuclease-aided aptamer walker
superoxidase dismutase, and catalase-like activity. Zhao et al. synthesized supramolecular
and the catalytic AuNPs [147]. Without targets, the aptamer bound to complementary strands of
functionalized AuNPs which possessed two enzyme-like properties using cyclodextrin as both the
aptamer on the AuNP surface and complementary strands would be degraded by the introduction
stabilizer and the reducing agent [142]. Moreover, the cyclodextrin-modified AuNPs were rather
of exonuclease, which led to the unmasking of the AuNP surface. As a result, 4-nitrophenol could
robust for the cascade reaction; reactions from glucose to gluconic acid and H2O2 (glucose oxidase-
approach the AuNP surface easily and induce a color change from yellow to colorless (Figure 14).
mimicking activity), to H2O and oxidized TMB (peroxidase-mimicking behavior), were catalyzed by
The strategy for the detection of zearalenone in a serum sample has also been proved.
the sole supramolecular functionalized AuNPs. Chen et al. developed a simple colorimetric strategy
for protein targets using aptamer–gold nanoparticle conjugates [143]. These conjugates included
catalytically active AuNPs for the amplification of the colorimetric readout response and anchored
aptamers for target recognition. In the presence of thrombin, the aptamer–thrombin interaction
effectively masked the catalytic AuNP surface and hampered the access of 4-nitrophenol to the
surfaces of AuNPs. Without thrombin, however, yellow 4-nitrophenol could freely attach to the
catalytic surface and turn to colorless 4-aminophenol. Based on this mechanism, the LOD was 0.1 nM
with the naked eye, which indicated an ultrahigh sensitivity assay. Similar approaches based on the
conversion of 4-nitrophenol to 4-aminophenol had been reported for the detection of other protein
targets [144–146]. Last year, Taghdisi et al. developed the amplified colorimetric aptasensor for
unmasking of the AuNP surface. As a result, 4-nitrophenol could approach the AuNP surface easily
and induce a color change from yellow to colorless (Figure 14). The strategy for the detection16of
Nanomaterials 2019, 9, 861 of 24
zearalenone in a serum sample has also been proved.
Figure
Figure TheThe
14.14. representation
representation of the
of the detection
detection of of zearalenone
zearalenone based
based on on
thethe exonuclease
exonuclease III-aided
III-aided
aptamer
aptamer walker
walker andand catalytic
catalytic reaction
reaction of AuNPs.
of AuNPs. Reproduced
Reproduced with
with permission
permission from
from Reference
Reference [147].
[147].
American Chemical Society,
American Chemical Society, 2018.2018.
6. Summary and Outlook

6. Summary and Outlook
The development of a simple and convenient biosensor for the detection of chemical and biological
The development of a simple and convenient biosensor for the detection of chemical and
agents is of significant importance. Compared with other sensing methods, AuNP-based colorimetric
biological agents is of significant importance. Compared with other sensing methods, AuNP-based
assays are promising because the whole assay proceeds through a simple solution of the target and
colorimetric assays are promising because the whole assay proceeds through a simple solution of the
probes without the washing steps, and the color change can be directly monitored with the naked eye
target and probes without the washing steps, and the color change can be directly monitored with
without sophisticated instruments. Therefore, these approaches remarkably simplify the operation
the naked eye without sophisticated instruments. Therefore, these approaches remarkably simplify
procedures, shorten the detection times, and significantly reduce the assay costs. Moreover, such
the operation procedures, shorten the detection times, and significantly reduce the assay costs.
colorimetric assays are easily adaptable to smartphone-based devices, which is a potentially powerful
Moreover, such colorimetric assays are easily adaptable to smartphone-based devices, which is a
platform to detect, transduce and analyze on-line sensing information [148–150]. Obviously, it will be
potentially powerful platform to detect, transduce and analyze on-line sensing information [148–150].
a good way to push colorimetric sensors forward with the integration of smartphone-based technique.
Obviously, it will be a good way to push colorimetric sensors forward with the integration of
In this review, we reported the recent developments in AuNP-based colorimetric methods including
smartphone-based technique. In this review, we reported the recent developments in AuNP-based
aggregation, etching, growth, and nanozyme for sensing applications. A large number of selected
colorimetric methods including aggregation, etching, growth, and nanozyme for sensing
examples of AuNP colorimetric assays have been introduced, and some novel and interesting strategies
applications. A large number of selected examples of AuNP colorimetric assays have been
with an outstanding sensor performance have been discussed. However, there are still some critical
introduced, and some novel and interesting strategies with an outstanding sensor performance have
issues that need to be addressed in the future. First, for many analytes such as tumor markers
been discussed. However, there are still some critical issues that need to be addressed in the future.
or antibiotics, the concentrations are commonly below the critical threshold levels, at which point
First, for many analytes such as tumor markers or antibiotics, the concentrations are commonly below
the biological and chemical targets are often undetectable by using current AuNP-based platforms.
the critical threshold levels, at which point the biological and chemical targets are often undetectable
To improve the sensitivity, various signal amplification methods have been rationally designed and
by using current AuNP-based platforms. To improve the sensitivity, various signal amplification
combined with the AuNP-based colorimetric approaches. However, these amplification processes
methods have been rationally designed and combined with the AuNP-based colorimetric approaches.
usually prolong the detection time and increase the experimental complexity. Thus, one of the future
However, these amplification processes usually prolong the detection time and increase the
directions of the field is to develop ultrasensitive AuNP-based colorimetric sensors without using
experimental complexity. Thus, one of the future directions of the field is to develop ultrasensitive
amplification processes. Second, the simultaneous detection of multiple analytes in the same solution
AuNP-based colorimetric sensors without using amplification processes. Second, the simultaneous
has attracted much attention because this method provides a significant advantage for rapid, simple,
detection of multiple analytes in the same solution has attracted much attention because this method
and reagent consumption. Although AuNP-based colorimetric sensors are extremely useful and simple,
provides a significant advantage for rapid, simple, and reagent consumption. Although AuNP-based
they are usually only employed in single-target assays. Advances in material science and analytical
colorimetric sensors are extremely useful and simple, they are usually only employed in single-target
techniques might design a new multicolor AuNP sensor to detect multiple targets in a one-pot reaction.
assays. Advances in material science and analytical techniques might design a new multicolor AuNP
Last but not least, although large-scale production of AuNPs for colorimetric sensing applications
sensor to detect multiple targets in a one-pot reaction. Last but not least, although large-scale
is well-established, their practical use in industry has not been explored yet. One possible reason
production of AuNPs for colorimetric sensing applications is well-established, their practical use in
is that many AuNP-based colorimetric assays are still at the proof-of-concept stage, and there is a
industry has not been explored yet. One possible reason is that many AuNP-based colorimetric
notable difference in the sensitivity and specificity of assays for analytes in pure systems versus in
complex samples. Furthermore, the background color of real sample solutions such as human serum
or industrial wastewater may interfere with the colored signal, which affects the accuracy of the assay.
Therefore, further explorations are required to investigate the possible applications of AuNP-based
colorimetric assays in clinical medicine and industry.
Typically, the development of AuNP-based colorimetric nanosensors has continued at a fast pace.
Even though challenges still exist, there is a scope for future research and the practical applications
of colorimetric strategies in environmental monitoring, chemical detection, biomedical analysis,
and healthcare diagnoses still need to be developed.
Author Contributions: Conceptualization, C.-C.C. and C.-Y.C.; investigation, T.-H.W., and C.-H.Y.;
writing—original draft preparation, C.-C.C., T.-H.W., and C.-H.Y.; writing—review and editing, C.-P.C. and
C.-W.L.; supervision, C.-C.C. and C.-Y.C; funding acquisition, C.-Y.C.
Funding: This work was supported by Mackay Memorial Hospital (MMH-108-10) and Ministry of Science and
Technology of Taiwan (MOST-106-2314-B-195-013-MY3).
Conflicts of Interest: The authors declare no conflict of interest.
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Gold Nanoparticle-Based Colorimetric Strategies For Chemical and Biological Sensing Applications

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nanomaterials

Nanomaterials 2019, 9, 861; doi:10.3390/nano9060861 www.mdpi.com/journal/nanomaterials

Figure 1. The summary of different types of gold nanomaterial-based colorimetric sensors.

2.1. Labeled Detection Methods

Nanomaterials 2019, 9, x FOR PEER REVIEW 3 of 24

2.1. Labeled Detection Methods

Figure 4. The different colloidal behaviors of ssDNA-labeled gold nanospheres,

Nanomaterials 2019, 9, x FOR PEER REVIEW 6 of 24

Nanomaterials 2019, 9, x FOR PEER REVIEW 7 of 24

Figure 6. The schematic representation of the measurement of dipeptidyl peptidase-IV(DPP-IV) activity.

3.2. Ion-Mediated Etching Reactions

4.2. Enzyme-Mediated Growth Reactions

6. Summary and Outlook

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