Abstract
This review (with 147 references) summarizes the state of the art in methods for signal amplification in immunoassays by using noble metal nanoparticles (MeNPs). Following an introduction into the field, a first large section covers MeNPs as signal tracers. The next sections describes the use of MeNPs as carriers for biomolecules, and of doped, decorated or functionalized MeNPs. A next large section covers MeNPs as used in aggregation-based assays that result in a change of color or dynamic light scattering (DLS). This is followed by a discussion of MeNPs that undergo etching, size reduction, or growth and thereby change color and DLS, with subsections on methods based on etching, particle growth or particle formation. We then rview methods where MeNPs acts as catalysts (enzyme mimics), with subsections on MeNPs and on doped or composed MeNPs. A final large section discusses the synergies of MeNPs or multiple signal amplification strategies in immunoassays. Several Tables are presented that give an overview on the wealth of methods and materials. A concluding section summarizes the current status, addresses current challenges, and gives an outlook on potential future trends.
Noble metal nanoparticles have been widely used as essential components of signal amplification strategies to enhance the sensitivity of the immunoassays. This review summarizes various signal amplification strategies using metal NPs serving as (a) signal tracers, (b) carriers, (c) aggregators, (d) enzyme mimics, (e) in growth or etching of NPs, and (f) in synergistic effects.
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Introduction
The sensitivity of any immunoassay is determined mainly by the intensity of the output signal. As the increasing demands for environmental monitoring [1], food safety analysis [2], disease diagnosis [3] and other research areas [4,5,6], novel signal amplification strategies are required to maximize the signal output. A variety of metal nanoparticles (NPs), or metal NPs doped by other materials have nontoxicity, chemical stability, fine biological compatibility, excellent catalytic activity and high surface-to-volume ratio. They have been widely used as essential components of signal amplification strategies to enhance the sensitivity of the immunoassays. They include magnetic bead [7], gold NPs (AuNPs) [8], silver NPs (AgNPs) [9], Fe3O4@SiO2 [4], Ag@bovine serum albumin (Ag@BSA) [10], zinc oxide nanoflower-bismuth sulfide composites (ZNF@Bi2S3) [11] and so on. With the development of nanotechnology, great attention has been paid to the combination of different nanomaterials to develop the signal amplification strategies. These strategies include magnetic NPs/aptamer/carbon dots nanocomposites [12], TiO2/S-BiVO4@Ag2S nanocomposites [13], MoS2-PEI-Au nanocomposites and Au@BSA core/shell NPs [14], N-GNRs-Fe-MOFs@AuNPs nanocomposites and AuPt-methylene nanorod [15]. Metal NPs with rich nanostructures not only load large number of signal elements such as antibody and enzyme, but also improve the electronic properties and produce detectable signals for indirect detection of targets, resulting high sensitivity of an immunoassay. Several reviews have been published focused on the synthesis, performance and applications of metal NPs in assay design [16,17,18,19,20,21,22], few dedicated to the signal amplification strategies in immunoassays. Here, we summarize selected articles from 2007 onwards on noble metal NPs as elements of signal amplification strategies in the development of immunoassays. Various signal amplification strategies using noble metal NPs are summarized in Fig. 1, such as serving as (a) signal tracers, (b) carriers, (c) aggregators, (d) enzyme mimics, (e) in growth or etching of NPs, and (f) in synergistic effects.
The roles of metal NPs in signal amplification in immunoassays
Noble metal NPs serving as signal tracers
Gold nanoparticles (AuNPs) have the distinguishing physical and chemical properties, such as biocompatibility, easy conjugation to biomolecules and better electrochemical or optical transduction property. They have become highly valuable nanomaterials in signal amplification strategies of immunoassay (Table 1). AuNPs labeled with antibody can act as the tracers for signal amplification by increasing amount of themselves in the position of detection line. Without any complicated labeling procedure, positively charged AuNPs-tracers can be directly bound to the negatively charged antibodies. Based on this mechanism, a large number of lateral flow assays utilizing antibody labeled positively charged AuNPs have been designed for different targets [23,24,25,26]. The AuNPs act as signal amplification tracers accumulate numerous AuNPs on test line which are correlated with the amounts of target in samples.
To further enhance the sensitivity, an AuNPs growth and accumulation signal amplification strategy based lateral flow assay was developed for rapid detection of Salmonella Enteritidis [27]. For having high catalytic activity, AuNPs produce new AuNPs on the surface of the initial AuNPs during the reaction between HAuCl4 and NH2OH·HCl. The remarkable enhanced signal can be clearly and visually distinguished even under a lower concentration of S. Enteritidis. The sensitivity (104 CFU/mL) is enhanced 100-fold compared to the traditional AuNPs based strategy (106 CFU/mL). This AuNPs growth and accumulation signal amplification strategy based assay need two “10 min reaction” steps (Fig. 2a).
Schematic diagram of metal NPs themselves as signal tracers. (A) AuNPs growth and accumulation signal amplification strategy based lateral flow assay. (a) principle of the signal amplification, (b) analysis process of the signal amplified lateral flow assay, (c) comparison pictures for enhancement effect illustration. Reproduced with permission from Ref. [27]. Copyright Elsevier, 2017. (B) Schematic illustration of the dual AuNPs-tracers based lateral flow assay. Reproduced with permission from Ref. [28]. Copyright Elsevier, 2010. (C) Schematic illustration of the dual labeling signal amplification strategy based lateral flow assay. Reproduced with permission from Ref. [29]. Copyright Elsevier, 2015
For signal amplification of lateral flow assay without an additional operation step, a strategy utilizing two AuNP-antibody conjugates was designed for detection of troponin I [28]. The 1st AuNPs-tracer was the AuNPs labeled with an anti-troponin I antibody and the 2nd AuNPs-tracer was the AuNPs labeled with an anti-BSA antibody. The 2nd AuNPs-tracer was designed to bind only with the 1st AuNPs-tracer with a higher size. Both two AuNPs-tracers act as signal amplification probes to aggregate numerous AuNPs on test line. The detection sensitivity (0.01 ng/mL) is increased about 100-fold compared to the conventional lateral flow assay (1 ng/mL) (Fig. 2b). Fang and coworkers designed a dual labeling signal amplification strategy using high affinity AuNPs-biotinylated anti-pesticide imidacloprid antibody (nanogold-BAb) and nanogold-streptavidin (nanogold-Sa) probe (Fig. 2c). The detection signal was the amount of nanogold-BAb and nanogold-Sa probes. The signal amplification was achieved by using nanogold-BAb probe for the determination of imidacloprid and nanogold-Sa probe for signal enhancement. The visual detection sensitivity and semi-quantitative analytical capacity of the assay are 10-fold and 160-fold higher than those of traditional lateral flow assay, respectively [29]. The immunochromatographic assays based on metal nanomaterials as signal tracers are simple, rapid and convenient to perform, and no equipments and professional analyst are required. Meanwhile, the sensitivities of these techniques are relatively lower compared to other assays.
Noble metal NPs serving as carriers
Noble metal NPs themselves as carriers for antibody, enzyme and other bio-molecules
Various material NPs, such as AuNPs, TiO2, as well as CuS-SiO2 have high surface areas, unique physicochemical properties, high chemical stability and ease to be functionalized. They have been used as carriers for loading different signal elements including antibodies, enzymes, oligo nucleotides and other bio-molecules [5, 7, 30,31,32,33,34,35,36,37,38,39,40,41,42,43] (Table 2).
Based on sandwich immunoreactions, AuNPs were used as labeling carriers of horseradish peroxidase (HRP)-antibody in combination with TMB as substrates. Parolo and coworkers designed a lateral flow format for detection of Human IgG used as model protein [44]. AuNPs have high surface areas of AuNPs, which load more amount of HRP than that of IgG. The signal amplification of catalytically oxidized substrate related to the concentration of targets is enhanced around 10-fold compared to the results that obtained just from the direct measurement of the AuNPs as non-modified tracers. Zhou’s group used AuNPs as carriers for loading antibody and HRP simultaneously, and developed a competitive immunoreaction format for detection of Pb(II) [45]. As low as 9 pg/mL of Pb(II) is still detectable, while for traditional IgG-HRP based ELISA only signal as high as 750 pg/mL of target is distinguishable [45]. Yin et al. designed an electrochemical immunoassay by using AuNPs as carrier for loading anti-His tag antibody labeled with HRP as signal amplification unit and methyl binding domain protein of MeCP2 as DNA CpG methylation recognization unit (Fig. 3a). After an immunoreaction, the AuNPs-IgG-HRP was captured on the electrode surface. Under the catalysis of HRP towards hydroquinone oxidized in the presence of H2O2, the amplified electrochemical reduction signal was produced [46].
Schematic diagram of metal NPs as carriers. a AuNPs as carrier for loading antibody, HRP and methyl binding domain protein of MeCP2 in electrochemical immunoassay. Reproduced with permission from Ref. [46]. Copyright Elsevier, 2013. b AuNPs as carrier for loading antibody and 6-carboxyfluorescein labeled single-stranded thiol-oligonucleotides in competitive fluorescence bio-barcode immunoassay. Reproduced with permission from Ref. [13]. Copyright Elsevier, 2017
On the basis of competitive immunoassay, Wang’s group proposed a bio-barcode amplification strategy for detection of small molecules, triazophos. In the assay, AuNPs were used as carrier for loading 6-carboxyfluorescein labeled single-stranded thiol-oligonucleotides and antibody. The targets in the sample compete with ovalbumin (OVA)-haptens coated on the bottom of microplate for binding to the antibody-AuNP-thiol-oligonucleotides. The fluorescence intensity quenched by AuNPs was inversely proportional to concentration of triazophos (Fig. 3b). The prominent advantage of the competitive fluorescence bio-barcode immunoassay is higher sensitivity than indirect competitive ELISA [13].
Noble metal NPs doped, decorated or functionalized with other materials as carriers or signal labels
To further enhance the sensitivity of immunoassays, metal NPs integrated with other materials have been employed as carriers to design various signal amplification strategies [47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. For example, using thionine (TH)-doped mesoporous ZnO nanostrawberries (MP-ZnO) for loading HRP labeled goat anti-human IgG (HRP-anti-IgG), and the immobilized ultralong Ag nanowires with the capture antibody (Fig. 4a), Cao et al. developed an electrochemical immunoassay for detection of human IgG [48]. The electrochemical signal of the sandwich-type immunoassay was significantly amplified due to crystalline framework, high surface area of the MP nanomaterials and the superconductivity of silver nanowires.
Schematic diagram of metal NPs doped or functionalized with other materials as carriers. (A) MP-ZnO functionalized with TH as carrier for loading HRP-anti-IgG in electrochemical immunoassay. (a) preparation procedure of MP-ZnO-TH for loading HRP-anti-IgG, (b) schematic view of electrochemical sandwich-type electrochemical immunoassay procedure. Reproduced with permission from Ref. [48]. Copyright Elsevier, 2013. (B) ZNF@Bi2S3 composites as carrier for loading capture antibodies in photoelectrochemical (PEC) immunoassay. Reproduced with permission from Ref. [11]. Copyright Elsevier, 2015. (C) Avidin functionalized Ru@SiO2 as signal labels in PEC immunoassay. (a) preparation procedure of avidin functionalized Ru@SiO2, (b) schematic view of PEC immunoassay procedure. Reproduced with permission. Reproduced with permission from Ref. [12]. Copyright Elsevier, 2018. (D) Au@BSA functionalized with luminol as carrier for loading Ab2 in electrochemiluminescence immunoassay. (a) formation of MoS2-PEI-Au nanocomposites, (b) preparation procedure of luminol-Au@BSA-Ab2 cojugation. Reproduced with permission from Ref. [14]. Copyright Elsevier, 2017. (E) Ag@BSA functionalized with HRP and Ab2 as carrier for loading tyramine in multi-enzyme assembly electrochemical immunoassay. (a) preparation procedure of HRP-Ag@BSA-Ab2, (b) schematic view of HRP-tyramine conjugate, (c) schematic view of multi-enzyme assembly electrochemical immunoassay. Reproduced with permission from Ref. [10]. Copyright Elsevier, 2013
Based on zinc oxide nanoflower-bismuth sulfide (ZNF@Bi2S3) composites materials and reduced graphene oxide (rGO), a photoelectrochemical (PEC) immunoassay was constructed for squamous cell carcinoma antigen (SCCA) detection [11]. In the assay, ZNF@Bi2S3 composites and rGO were used as photoactive materials and signal labels respectively. HRP was used not only to block nonspecific binding sites, but also participate in luminol-based chemiluminescence (CL) system to induce inner light source. The induced CL emission acted as an inner light source excited photoactive materials. The rGO trigged the CL resonance energy transfer between luminol and rGO which decreased the efficient of CL emission to ZNF@Bi2S3 composites and electrons amount to electrode surface. The steric hindrance, increased by the introduced rGO-Ab2 hindered the electron donor to the surface of Bi2S3 for reaction with the photogenerated holes (Fig. 4b). This novel signal amplification strategy based PEC immunoassay exhibits low detection limit, good reproducibility and wide linear ranges. Based on avidin functionalized Ru@SiO2 and carboxylated g-C3N4(CN), Ai and Yin’s group constructed another PEC immunoassay [12]. In the assay, N6-methyladenosine-5′-triphosphate (m6ATP), Ru@SiO2 and CN were used as the detection target molecule, signal amplification unit to improve the photocurrent and the support for the antibody immobilization, respectively. Phos-tag-biotin was employed as bridge of target and Ru@SiO2 (Fig. 4c). The sensitivity of the PEC immunoassay is improved by the specific interaction between Phos-tag and phosphate group, biotin and avidin.
Metal NPs have been doped with other materials, such as AuNP-doped BSA microspheres (Au@BSA) [14], nanosilver-doped BSA microspheres (Ag@BSA) [10] and AuNP-doped mesoporous SiO2 (Au/SiO2) [62]. They can be employed as carrier for loading numerous molecule recognition antibody, HRP or luminol molecules in electrochemical immunoassays. For example, Zhang and coworkers developed a sandwich-type electrochemiluminescence immunoassay for the detection of alpha fetal protein (AFP) by using luminol-Au@BSA NPs to load secondary antibodies (Ab2) and luminol molecules [14]. In the assay, the MoS2 nanosheets were labeled with polyethylenimine (PEI) polymer and AuNPs were electrostatically adsorbed to form MoS2-PEI-Au nanostructures. The target molecules were sandwiching captured by the primary antibody (Ab1) and the luminol-Au@BSA-Ab2 nanocomposite through specific immunoreactions (Fig. 4d). The electrochemiluminescence signal amplification was achieved by the catalytic performance of MoS2-PEI-Au nanocomposites. Zhou and coworkers assembled a HRP-tyramine conjugates electrochemical immunoassay based on nanosilver-doped BSA microspheres (Ag@BSA) and glassy carbon electrode for detection of carcinoembryonic antigen (CEA). HRP and detection antibody were immobilized on the surface of Ag@BSA (Fig. 4e). The signal amplification was obtained by coupling enzymatic biocatalytic precipitation with tyramine and carbon electrode modified with capture antibody [10]. The multi-enzyme assembly electrochemical immunoassay exhibits higher sensitivity in comparison with traditional Ag@BSA labeling method.
The sensitivities of these methods were improved by employing metal NPs as bio-molecules carrier because the metal NPs offer an opportunity to load a large amount of biomolecules, such as enzymes improving the sensitivity of the assay. However, the stability of metal NPs based probes in immunoassays are comparable lower than those of IgG-enzyme conjugates. And the synthesis procedures of metal NPs probe are time-consuming and labor-intensive. Table 2 summarizes the main characteristics of these methods.
Noble metal NPs serving as aggregations
Localized surface plasmon resonance (LSPR) is the most remarkable inherent optical properties of AuNPs and AgNPs. Colloidal solutions of AuNPs and AgNPs have different colour in the visible spectrum region when they are well spaced in comparison with when they are aggregated. Therefore, designed immunoreactions between the analyte and the metal NPs can lead to a colour change of the solution. The aggregations of AuNPs and AgNPs change the colour of colloidal solution from red to purple-blue and from yellow to brown respectively allowing the visual detection of the target analyte [21] (Table 3).
Noble metal NPs as aggregations induced by addition of target analyte to trigger the change of colour and DLS of the solution
Based on aggregation of antibody-functionalized NPs coupled with DLS, sandwich type format (NPs-Ab1-analyte-Ab2-NPs) metal NPs aggregation assays (NanoDLSays) are used as a model to establish the general immunoassays in the fields of molecular biology [66, 67], food analysis [68] and clinical diagnostics [69, 70]. Zhou’s group proposed a NanoDLSay by using functionalized AuNPs with anti-β-casein mono- (McAb) and polyclonal (PcAb) antibodies, respectively as probes for detection of β-casein in bovine milk [68]. After addition of sample to the AuNPs probes, aggregation of AuNPs occurred through sandwich type format immunoreactions. The β-casein triggered AuNPs aggregation resulted in an obvious colour change from red to blue which was also monitored with DLS (Fig. 5a). Huo designed a NanoDLSay by using anti-prostatic acid phosphatase (PAP) McAb labeled with AuNPs as probes for examine of PAP (Fig. 5b), a potential biomarker for prostate cancer detection and diagnosis [69].
Schematic diagram of AuNPs as aggregations induced by target analyte. a Schematic diagram of AuNPs functionalized by anti-β-casein McAb and PcAb, respectively as probes in NanoDLSay. Reproduced with permission from Ref. [68]. Copyright Elsevier, 2014. b Schematic diagram of AuNPs functionalized by anti-PAP McAb as aggregations in NanoDLSay. Reproduced with permission from Ref. [69]. Copyright Elsevier, 2010
Noble metal NPs as aggregations induced by enzyme to trigger the change of colour and DLS of the solution
Enzyme-mediated aggregation of AuNPs in plasmonic ELISA (P-ELISA) has received considerable attention because it allows a naked-eye detection of target in very low numbers. Based on HRP-mediated AuNPs aggregation, Xiong’s group integrated a P-ELISA for highly sensitive detection of ochratoxin A (OTA) [71]. In this assay, anti-OTA McAb was used as a coating antibody and OTA-labeled catalase (CAT) conjugate (OTA-CAT) was used as competing antigen to consume H2O2. AuNPs aggregation was triggered through the phenol polymerization of tyramine (TYR), which was induced by hydroxyl radicals from HRP-catalyzed H2O2. The color response generated through AuNPs aggregation (Fig. 6a). The signal output was amplified by ultrahigh CAT catalytic activity for H2O2. The designed P-ELISA exhibit a high sensitivity for OTA quantitation with a cut-off limit of 150 pg/mL visually. Based on acetylcholinesterase (AChE)-mediated aggregation of AuNPs, Nie and coworkers developed an ultrasensitive P-ELISA for the detection of total antibodies to T. pallidum [72]. The immunoreactions of the target antibodies were triggered by the AChE-catalyzed hydrolysis of acetylthiocholine to produce thiocholine which changed the surface charge distribution on the AuNPs and lead to the agglomeration of the AuNPs (Fig. 6b). The induced changes of DLS allowed the quantitative assay of T. pallidum antibodies. The sensitivity (0.89 × 10−12 g/ml) is 1000-fold improvements in sensitivity over a conventional ELISA (1.0 × 10−9 g/ml).
Schematic diagram of enzyme-mediated aggregation of AuNPs in P-ELISA. a Schematic diagram of HRP-mediated AuNPs aggregation for detection of OTA. Reproduced with permission from Ref. [71]. Copyright Elsevier, 2017. b Schematic diagram of AChE-mediated aggregation of AuNPs for detection of anti-T. pallidum antibodies. Reproduced with permission from Ref. [72]. Copyright Elsevier, 2014
The major limitation of the aggregations based immunoassays is ‘autoaggregation’. external factors, such as pH, ionic strength and temperature may induce undesirable aggregation of metal nanoparticles, and then result in high backgrounds or false positive results.
Noble metal NPs serving as in etching or growth of NPs
The LSPR extinction of AuNPs and AgNPs is strongly dependent upon the diameter, morphology, composition, the surrounding media, and aggregation state of the NPs [16]. Through mediated etching or growth of the NPs, enhanced signal amplification linearly correlated with the concentrations of analytes can be achieved [73, 75, 76] (Table 4).
Noble metal NPs by etching to change the colour and DLS of the solution
Based on alkaline phosphatase (ALP)-triggered etching of gold nanorods (AuNRs), Zhang and coworkers designed a P-ELISA for highly sensitive colorimetric detection of human IgG [55]. As the sandwich-type immunocomplex formation reaction, the ALP labeled on the antibody hydrolyzed ascorbic acid 2-phosphate into ascorbic acid. Subsequently, iodate was reduced to iodine which etched AuNRs from rod to sphere in shape, leading to a blue-shift of LSPR (Fig. 7a). The visual P-ELISA achieved a naked-eye detectable limit of 3 ng/mL of human IgG. Based on CAT-triggered etching of triangular silver nanoprisms (AgNPRs), Yao and coworkers designed an AgNPRs etching P-ELISA for colorimetric determination of Cr (III) in environmental water samples. H2O2 was used to etch triangular AgNPRs into spherical AgNPRs, inducing a change in color and the LSPR wavelength shift of the AgNPRs reaction solution. The reaction was achieved by controlling H2O2 concentration that remains after degradation by CAT which was labeled with an Ab2. The color change and the LSPR wavelength shift were closely correlated with the concentration of Cr (III). The developed P-ELISA can be used for the quantitative detection of Cr (III) with a limit of detection (LOD) of 3.13 ng/mL through the LSPR wavelength shift of the solution. They also can be used for the visual detection of Cr (III) with a sensitivity of 6.25 ng/mL indicated by a color visual change [77]. Also based on AgNPRs etching principle, Tang’s group proposed a glucose oxidase (GOx)-triggered P-ELISA for the detection of cancer biomarkers [78]. In the assay, GOx catalysed oxidation of glucose to produce H2O2 which acted as an oxidant to etch the AgNPRs into smaller spherical silver NPs (Fig. 7b). The reaction was accompanied by substantial blue shift of the LSPR and change of colour of the solution. The AgNPRs-etched P-ELISA can be used for the detection of cancer biomarkers in the concentrations from 10 fg/mL to 100 pg/mL.
Schematic diagram of AuNRs and AgNPRs etching in P-ELISA. a Schematic diagram of ALP-triggered etching of AuNRs. Reproduced with permission from Ref. [55]. Copyright American Chemical Society, 2015. b Schematic diagram of GOx-triggered etching of AgNPRs. Reproduced with permission from Ref. [78]. Copyright Elsevier, 2015
Noble metal NPs by growth to change the colour and DLS of the solution
Based on ALP-mediated growth of AgNPs, Xuan and coworkers developed a visual P-ELISA for sensitive and rapid detection of cancer biomarkers in clinical serum samples [79]. In the assay, ALP was bound to the detection antibody and the AgNPs were integrated with ALP, which hydrolyzed ascorbic acid-phosphate to produce reductant ascorbic acid. Subsequently, the ascorbic acid reacted with silver ions to produce metal silver which nucleated to become silver nanocrystals. The further growth of silver nanocrystals resulted in the formation of larger sized AgNPs (Fig. 8a). As a consequence, the colorless solution turned yellow along with the appearance of an absorption band at around 400 nm. The color intensity of the solution as well as their corresponding absorbance was proportional to the concentrations of analytes. Based on GOx-catalyzed growth of AuNPs, Liu and coworkers described a quantitative colorimetric immunoassay for ultrasensitive detection of cancer biomarkers [80]. The surfaces of magnetic beads (MBs) were modified with detection antibody (Ab2) labeled by GOx which can generate H2O2. After a sandwich immunoreaction on the polystyrene substrate, the captured target pulled down the Ab2-GOx-MBs conjugates on the substrate, where the GOx catalyzed the oxidation of glucose to produce H2O2. The produced H2O2 lead the growth of AuNPs in the presence of AuCl4−, resulting the colour and DLS changes of the solution (Fig. 8b).
Schematic diagram of AgNPs and AuNPs growth in immunoassay. a Schematic diagram of ALP-mediated growth of AgNPs. Reproduced with permission from Ref. [79]. Copyright Royal Society of Chemistry, 2016. b Schematic diagram of GOx-catalyzed growth of AuNPs. Reproduced with permission from Ref. [80]. Copyright American Chemical Society, 2014
Noble metal NPs by adjust the formation of AuNPs to change the colour and DLS of the solution
Based on reduction HAuCl4 to form AuNPs, Huang’s group fabricated an ethylene diamine tetraacetic acid (EDTA)-triggered assay for detection of disease biomarker and drug [81]. In the assay, the analyte-recognizable antibody was labeled with EDTA which catalyzed decomposition of H2O2 and adjusted the growth of H2O2-induced formation of AuNPs with color variation. Through combining with a sandwich immunoassay, a various color AuNPs suspension can be obtained as a read-out means (Fig. 9). The fabricated sensitive assay allows for naked-eye detection of cancer antigen15-3 and small molecular drug methamphetamine with high accuracy.
Schematic diagram of ELISA-like assay based on EDTA-triggered AuNPs formation. Reproduced with permission from Ref. [81]. Copyright Elsevier, 2017
In the growth based immunoassay, the factors including ageing of the solutions, type of reaction vessel and reaction scale of the system can interfere and result in false positive results. The etching based immunoassay is the mainly robust to the field conditions compared to other approaches such as aggregations, growth and metallization of NPs.
Noble metal NPs serving as catalysts (enzyme mimics)
Noble metal NPs itself as catalysts (enzyme mimics) to catalyze substrates to trigger a detectable signal
Wei and Wang reviewed various NPs with enzyme-like characteristics mainly focused on their kinetics, mechanisms, the activity tuning of catalysts, as well as applications in numerous fields [82]. Metal NPs not only can enhance the activities of HRP [83], but also have unique peroxidase-like activity which can catalytic oxidation of peroxidase substrate 3,3,5,5-tetramethylbenzidine (TMB) with H2O2 [84]. These findings open up a wide range of new potential applications of metal NPs in immunoassays.
Metal NPs, such as Pt, Au and Ag NPs have more active sites on their surface than enzymes, usually just only one site. Thus, when they are used as enzyme mimics, signals are generated at many active sites per NP allowing higher signal amplification [85,86,87,88,89]. Gao and coworkers first reported the intrinsic peroxidase-like activity of Fe3O4 NPs which catalysed the reaction of peroxidase substrates to give the same colour changes as HRP. The catalysis showed typical Michaelis-Menten kinetics and H2O2, pH and temperature dependence. Based on this finding, they proposed a novel immunoassay by using Fe3O4 NPs as functions of capture, separation and detection tools [90]. Duan and coworkers developed a nanozyme-strip for the detection of Ebola virus by using Fe3O4 NPs as a nanozyme probe [91]. The diagnostic accuracy for clinical samples is comparable with ELISA, while the performance of the nanozyme-strip is much faster (within 30 min) and simpler (without need of any equipments and specialist). The sensitivity (1 ng/ml) is 100-fold more sensitive than that of traditional lateral flow assay (100 ng/ml). Syed Rahin Ahmed and coworkers also designed a modified ELISA for the detection of Influenza Virus by using the peroxidase-mimic of AuNPs for signal amplification (Fig. 10). The sensitivity improves to 500-fold higher than that of commercial virus kits [87].
Schematic diagram of peroxidase-mimic enzymatic reaction of AuNPs. a viruses coated on a polystyrene 96-well plate, b antibody-AuNPs conjugate bound with virus through immunoreactions, c TMB-H2O2 added and d color changes due to peroxidase-mimic activity of AuNPs. Reproduced with permission from Ref. [87]. Copyright WILEY-VCH, 2016
Noble metal NPs doped or combining with other nanomaterials as catalysts to catalyze substrates to trigger a detectable signal
Natural enzymes have critical limitations for immunoassay application, such as low stability under harsh temperature and pH conditions. To overcome these limitations, various nanostructures have been synthesized as enzyme mimics for signal amplification of immunoassay. Nanohybrids with nanostructures exhibit amazing synergistic effects to enhance the catalytic activity that can be used in the field of biosensors and immunoassays. The combing nanostructures of metal NPs with other material as artificial enzymes have been intensively studied for colorimetric and electrochemical immunoassays [4, 86, 92,93,94,95].
For example, Wang and coworkers fabricated a powerful enzyme mimic by loading Pt nanocatalysts on hydrophobic carbon nanotubes (CNTs) which were dispersed in graphene oxide (GO) nanocolloids. The nanohybrids exhibits greatly enhanced peroxidase-like catalysis comparable to natural enzymes. An electrochemical immunoassay has been successfully developed using the nanohybrids GO-CNT–Pt as catalysts [94]. Park’s group synthetized a hybrid structure of graphene-AuNPs and designed a colorimetric immunoassay by using antibody conjugated graphene-AuNPs for sensitive detection of norovirus-like particles in human serum (Fig. 11a). The sensitivity (92.7 pg/mL) is 112 times higher than that of a conventional ELISA (10.4 ng/mL) [92]. Park’s group also produced nanohybrids composed of AuNPs and CNTs. The AuNP-CNT nanohybrids shows enhanced peroxidase-like catalytic activity which is used as part of an ultrasensitive colorimetric test for influenza virus A (Fig. 11b). The detection limit (3.4 PFU/ml) shows 385 times lower than that of conventional ELISA (1312 PFU/ml) [93].
Schematic diagram of AuNPs combining with other nanomaterials as catalysts. a Schematic illustration of graphane-AuNPs nanohybrids as enhanced peroxidase-like catalysis in colorimetric immunoassay. Reproduced with permission from Ref. [92]. Copyright Elsevier, 2017. b Schematic illustration of CNTs-AuNPs nanohybrids as enhanced peroxidase-like catalysis in colorimetric test. Reproduced with permission from Ref. [93]. Copyright Elsevier, 2016
Based on N-doped graphene nanoribbons immobilized Fe-based-Metal-organic frameworks deposited with AuNPs (N-GNRs-Fe-MOFs@AuNPs) nanocomposites, Tang and coworkers designed a sensitive sandwich-type electrochemical immunoassay for the detection of galectin-3 (Gal-3) [15]. A glassy carbon electrode (GCE) was modified with AuNPs immobilized by Ab1 against Gal-3. Methylene blue (MB) as an electron transfer mediators was responsible for electron production and signal amplification. The Ab2 against Gal-3 was combined with AuPt-MB nanohybrids which displayed redox-active, uniform morphology and good electrochemical activity to generate and amplify the electrochemical signal. The sandwich type format of N-GNRs-Fe-MOFs@AuNPs-Ab1 coupled with AuPt-MB-Ab2 greatly enhanced the immunoassay’s sensitivity (Fig. 12).
Schematic diagram of doped metal NPs nanocomposites as catalysts in sandwich-type electrochemical immunoassay. Reproduced with permission from Ref. [15]. Copyright Elsevier, 2017. a Schematic illustration of N-GNRs-Fe-MOFs@AuNPs. b Schematic illustration of AuPt-MB-Ab2
Fe3O4 NPs coupling with other nanomaterials, can accelerate catalytic activity in various signal amplification strategies in electrochemical immunoassays [1, 96,97,98]. For example, Wei and coworkers fabricated an ultrasensitive photoelectrochemical (PEC) immunoassay for the detection of microcystin-LR (MC-LR) based on Fe3O4 NPs/ polydopamine (Fe3O4@PDA) which was used as the label carrier to conjugate the Ab2 and HRP. CdS/TiO2 nanorod arrays, having high photo-to-current conversion efficiency were used as a sensitive PEC material to immobilize antigens. After the specific immunoreaction of MC-LR with its antibody, the photocurrent change was amplified due to the synergistically accelerate catalytic activity of Fe3O4 NPs and HRP on the electrode surface [1]. Wu and coworkers designed an ultrasensitive electrochemical immunoassay by using the synergetic effect of dumbbell-like Pt-Fe3O4 NPs in catalyzing H2O2 reduction for squamous cell carcinoma antigen (SCC-Ag) [98]. The Ab1 specific for SCC was immobilized onto nitrogen-doped graphene sheets modified glassy carbon electrode. The Pt-Fe3O4 NPs were used as carrier for loading the Ab2 (Fig. 13a). The synergetic effect of Pt-Fe3O4 NPs results in the high sensitivity of the assay. Liu’s group also developed a highly sensitive electrochemical immunoassay for detection of chlorpyrifos. The glass carbon electrode was modified with polydopamine nanospheres (PDANSs) as the assay platform. Fe3O4 NPs was coated on CNTs as the signal label. The flake-like CNTs@f-Fe3O4 nanocomposites possessing large surface area was used as carrier for loading abundant of Ab2 and HRP (Fig. 13b). The high sensitivity of the assay is achieved attributed to the peroxidase-mimic activity of Fe3O4 [96].
Schematic diagram of catalytic activity of Fe3O4 NPs combining with other nanomaterials as catalysts in electrochemical immunoassay. a Schematic illustration of dumbbell-like Pt-Fe3O4 NPs in catalyzing H2O2 reduction. Reproduced with permission from Ref. [98]. Copyright Elsevier, 2013. b Schematic illustration of flake-like CNTs@f-Fe3O4 nanocomposites as peroxidase-mimic activity. Reproduced with permission from Ref. [96]. Copyright Elsevier, 2015
The enzyme activity of metal NPs is mainly dependent on particle size. After loading more biomoleculars, the enzyme activity of metal NPs decrease even disappear. These limit the usage of metal NPs as enzyme mimics in immunoassays. Table 5 sumarizes the metal NPs used as catalysts.
Noble metal NPs serving as in synergistic effects
Metal NPs have synergistic effect for biocompatibility and conductivity to enhance signal transduction producing amplify recognition events with designed signal tags. Association of different metal NPs or metal NPs with other nanocomposits can escalate the signal amplification effect [100, 101]. For instance, utilizing the superior photoelectric properties of Zinc Oxide (ZnO) and the better electron transportation property of AuNP, the amalgamating ZnO with AuNP can result in more sensitive response against SK-BR-3 cancer cells [102] and Carcinoembryonic antibody [103]. Several metal NPs have been simultaneously employed in one or multiple signal amplification strategies in an immunoassay [6, 13, 104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129] (Table 6).
Using ZnO-label/cadmium sulfide (CdS)-staining and enhanced cathodic preconcentration/in-situ anodic stripping voltammetry (ASV) analysis of the stained CdS, Qin and coworkers fabricated an ultrasensitive metal-labeled amperometric immunoassay for human IgG and human heart-type fatty-acid-binding protein. In the assay, the glassy carbon electrode (GCE) was modified with β-cyclodextrin-graphene sheets (CD-GS) nanocomposite. BSA, Ab1, antigen and ZnO-multiwalled carbon nanotubes (MWCNTs) labeled Ab2 (Ab2-ZnO-MWCNTs) were anchored on the CD-GS nanocomposite through an immunoreaction, forming a sandwich-type immunoelectrode (Ab2-ZnO-MWCNTs/antigen/BSA/Ab1/CD-GS/GCE). The following in-situ ASV detection was used for sensitive enhanced immunoassay [6]. Feng and coworkers fabricated a PEC immunoassay based on TiO2/S-BiVO4@Ag2S composites by layer-by-layer method for quantitative detection of the ochratoxin A (OTA). TiO2 has good photoelectric activity and large surface area. The S-BiVO4 has porous structure surfaces which is beneficial for the sufficient in-situ growth of Ag2S NPs with high absorb visible-light. The cascade band-edge levels of assembled TiO2/S-BiVO4@Ag2S composites promote ultrafast transfer of charge and effectively inhibited the recombination of e−/h + pairs. Consequently, the response of photocurrent was enhanced and the conversion efficiency of photocurrent was improved [13]. Based on Graphene/chitosan-ferrocene (GO/CS-Fc) and Fe3O4/AuNPs as the assay platform, Peng and coworkers designed a novel electrochemical immunoassay for the detection of carcinoembryonic antigen (CEA). Due to possessing high surface area, GO/CS-Fc was used as carrier for loading a large amount of Ab1. Fe3O4/AuNPs were labeled with Ab2. After the immunoreactions, a sandwich structure GO/CS-Fc/Ab1-CEA-Ab2/Fe3O4/AuNPs was formed. The redox cycling efficiency was enhanced by introducing the Fe3O4/AuNPs/Ab2 onto the electrode surface (Fig. 14). Based on the redox cycling amplification strategy, the detection signal (30 μA) is 10-fold increased compared to that without Fe3O4/Au NPs labeling (3 μA) [130].
Schematic diagram of GO/CS-Fc and Fe3O4/AuNPs based electrochemical immunosensor. Reproduced with permission from Ref. [130]. Copyright Elsevier, 2015
Using gold-silver hollow microspheres (AuAgHSs) as labels, Tang and coworkers fabricated a dual signal amplification strategy in electrochemical immunoassay for the detection of carcinoembryonic antigen (CEA used as model analyte) [106]. The amplification of the electrochemical signal was based on the catalytic recycling of the product with the aid of the labeled GOx on the AuAgHSs and the immobilized prussian blue nanoparticles (PBNPs) on the graphene nanosheets. With a sandwich-type immunoassay on the graphene-based platform, the first signal amplification was introduced based on the catalytic oxidation of glucose by GOx labeled on the AuAgHSs. The generated H2O2 was catalytically reduced by PBNPs immobilized on the electrode with the second amplification. Lin and coworkers also designed a dual signal amplification strategy based electrochemical immunoassay for ultrasensitive detection of benzo[a]pyrene (BaP). Fe3O4/polyaniline/Nafion (Fe3O4/PANI) nanocomposites were assembled on the surface of Nafion/ITO as assay platform to capture BaP. Fe3O4 NPs in the Fe3O4/PANI nanocomposites served as a mimetic peroxidase to catalyze the reduction of H2O2, providing a good pathway of electron transfer. Highly-carbonized spheres (HCS) were used as nanocarrier for loading HPR and Ab2. After competitive immunoreactions between the BaP on the assay platform and BaP in the sample solution with the Ab1, multi-HRP-HCS-Ab2 label was capture by Ab1 on the assay platform (Fig. 15a). The enhanced signal of catalytic current was achieved by using Fe3O4/PANI nanocomposites as the multiplex binding biomimetic peroxidase for the reduction of H2O2 [97].
Schematic diagram of different metal NPs in signal dual-amplification strategy. a Schematic illustration of Fe3O4/PANI nanocomposites based electrochemical immunoassay. Reproduced with permission from Ref. [97]. Copyright Elsevier, 2012. b Schematic illustration of MBs-ALP-triggered AuNPs aggregation in P-ELISA. Reproduced with permission from Ref. [113]. Copyright Elsevier, 2017
Combing the high loading capacity of MBs for ALP and ALP-triggered dispersion of aggregated AuNPs, Zhan and coworkers proposed a dual-signal amplified P-ELISA for sensitive detection of respiratory syncytial virus [113]. In this assay, MBs were employed as carrier to load large amount of ALP molecules for signal amplification. The introduction of Zn2+ to the detection system induced the accelerated dephosphorylation reaction of ALP to trigger the dispersion of aggregated AuNPs, resulting in the amplification of the signal (Fig. 15b). The sensitivity of the P-ELISA (0.021 pg/mL) exceed that of conventional ELISA (1 pg/mL) by about 50 times.
Based on both AuNPs and electro-active indicator labeled rolling circle amplification, Su and coworkers developed a multiple signal amplification electrochemical immunoassay for the detection of alpha-fetoprotein. In the assay, AuNPs were used as carrier for loading a large amount of primary DNA, Pt NPs were used as the carrier of ferrocenemonocarboxylic (Fc) and HRP. After an immuno-sandwich protocol, the conjugates of primary DNA and Ab2 acted as a precursor to initiate rolling circle amplification. The enzymatic signals were amplified by the catalysis of HRP and Pt NPs with the addition of H2O2. The multiple amplified signals lead to low detection limit of alpha-fetoprotein [105]. Based on enzyme-mediated AuNP growth and silica NPs carrying poly acrylic acid nanospherical brushes (SiO2@PAA@CAT/GOx), multiple signal amplification strategy P-ELISAs have been developed [127, 131, 132]. For example, based on CAT-mediated AuNP growth and silica NPs carrying poly acrylic acid nanospherical brushes (SiO2@PAA@CAT), Huang and coworkers designed a P-ELISA for ultrasensitive detection of disease-related biomarker ochratoxin A (OTA) by using sandwich formats [131]. SiO2@PAA was not only served as a “CAT container” (SiO2@PAA@CAT) to generate a signal amplification, but also used as a regulator to adjust the binding ability between competitive antigens and antibodies because of its relatively greater volume weight (Fig. 16). The LODs of the proposed P-ELISA are at least 7 orders lower than that of competitive CAT-based P-ELISA (by the naked eye) and 8 orders lower than that of HRP-based conventional ELISA (by the microplate reader), respectively. Based on the same principle, Zhang and coworkers proposed another P-ELISA using SiO2@PAA@GOx nanospherical brushes for detection of Typical Tetrabromobisphenol A Derivative and Byproduct [132]. The sensitivity of the method (3.3 × 10−4 μg/L) is 3 orders of magnitude higher than that using conventional colorimetric ELISA with the same antibody (0.7018 μg/L).
Schematic diagram of SiO2@PAA@CAT@OTA based P-ELISA. Reproduced with permission from Ref. [131]. Copyright American Chemical Society, 2016. a Schematic illustration of SiO2@PAA@CAT@OTA preparation, b Schematic diagram of P-ELISA based on CAT-catalyzed growth of AuNPs
Although the synergistic effects of metal NPs can escalate the signal amplification of the assay. Association of more metal NPs or other nanocomposits makes the system of the assay more complicated.
Conclusions and perspectives
Considerable progresses of noble metal NPs based signal amplification strategies in immunoassays have been made in recent years. However, the following significant issues are still deserved in-depth exploration. (1) Integration of different techniques. The integration of metal NPs based signal amplification strategies with other techniques, such as nanofluidics, electrochemistry, molecular biology, biophysics and multiplexing methodologies provide possibilities for fabrication of new ultrasensitive immunoassay. (2) Combining of multiple signal amplification strategies. The combination of different signal amplification strategies in one immunoassay is an avenue for development of new ultrasensitive immunoassay. (3) Generation of new nanohybrids. To generate new nanohybrids with enhanced catalytic activity, higher stability and lower toxicity for signal amplification strategy applications is also highly desirable. (4) Synergy research for noble metal NPs each other or with other nanomaterials. The synergy research both in experiments and theories is needed for fundamental understanding and better applications of noble metal NPs in signal amplification strategy. Using synergies of noble metal NPs each other or with other nanomaterials should be tailored for the design of novel signal amplification strategy.
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Acknowledgements
The authors are thankful to the financial support of the National Key R&D Program of China (grant numbers 2018YFC1602500, 2017YFC1601205) and the National Natural Science Foundation of China (grant numbers 31601536, 31871888).
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Yang, H., Xu, W. & Zhou, Y. Signal amplification in immunoassays by using noble metal nanoparticles: a review. Microchim Acta 186, 859 (2019). https://doi.org/10.1007/s00604-019-3904-9
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DOI: https://doi.org/10.1007/s00604-019-3904-9