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[Yoshitaka Shingaya](https://orcid.org/0000-0002-5926-3302), Hirokazu Takaki, Nobuhiko Kobayashi, [Masakazu Aono](https://orcid.org/0000-0002-4058-8967), [Tomonobu Nakayama](https://orcid.org/0000-0001-9696-475X)

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[Single-molecule detection with enhanced Raman scattering of tungsten oxide nanostructure](https://mdr.nims.go.jp/datasets/8f2e5e53-f791-43d8-b775-0c5bc8e28bff)

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Single-molecule detection with enhanced Raman scattering of tungsten oxide nanostructureNanoscalePAPERCite this: DOI: 10.1039/d2nr03596kReceived 1st July 2022,Accepted 21st August 2022DOI: 10.1039/d2nr03596krsc.li/nanoscaleSingle-molecule detection with enhanced Ramanscattering of tungsten oxide nanostructure†Yoshitaka Shingaya, *a Hirokazu Takaki, b Nobuhiko Kobayashi, bMasakazu Aono a and Tomonobu Nakayama *a,bWe have found that tungsten oxide nanorods have a very large enhancement effect on Raman scattering.The nanorods with adsorbed 12CO and 13CO at the ratio of 1 : 1 were dispersed on a Si substrate andRaman mapping was performed. The Raman images of 12CO and 13CO were completely different, indicat-ing that a very small number of molecules at the single-molecule level were observed. We also confirmedthe characteristic blinking phenomenon when single-molecule detection was performed. The very largeenhancement effect of Raman scattering can be attributed to the {001}CS structure of the tungsten oxidenanorods. It was confirmed from the DFT calculation results that the {001}CS structure exhibits two-dimensional electrical conduction properties.1. IntroductionRaman scattering spectroscopy is a powerful method of identify-ing molecular species or obtaining information of the environ-ment of molecules.1 However, an extremely small cross section2of Raman scattering makes it difficult to realize single-mole-cule-level detection sensitivity, which is required for certaintypes of application such as medical diagnostics,3 water orenvironmental monitoring4 and food safety monitoring.5Surface enhanced Raman scattering (SERS) can greatly amplifyRaman signals as already demonstrated using roughened sur-faces of Ag, Au or Cu6–8 or their nanoparticles. SERS with extre-mely high sensitivity has been realized with Ag nanoparticleaggregates, eventually demonstrating single-molecule-leveldetection sensitivity.9–11 The extremely large enhancementeffect observed is mainly due to the surface plasmon resonancein a nanogap region between two adjacent Ag nanoparticles.12,13Considerable efforts have been devoted so far to optimizinginter-nanoparticle distances14–16 or shapes of noble-metalislands on insulating substrates17 to maximize the enhance-ment effect. To date, metals for obtaining a substantial SERSeffect have been limited to noble metals such as Ag and Au.In recent years, plasmonics based on semiconductingmaterials such as metal oxides, metal chalcogenide and metalnitrides have attracted considerable attention.18–20 Titaniumnitride nanoparticles for photothermal conversion,21 tunablelocalized surface plasmon resonance using indium tin oxidenanoparticles22 or tungsten oxide nanocrystals,23 epsilon-near-zero materials using tungsten bronze24,25 and photo catalyticreaction using molybdenum oxide or tungsten oxide26–28 havebeen reported. SERS effect using semiconducting nanocrystalshas also been reported,29–33 however, the enhancement factoris not very large and single-molecule detection is notachievable.In this paper, we report that a metal oxide nanorod, anintermediate oxide of tungsten, WOx (x < 3),34–36 shows anextremely large enhancement effect of Raman scattering, andwe also show that single-molecule detection becomes possibleby using a certain activation procedure. Carbon monoxide(CO) adsorbed on WOx is clearly detected through the C–Ostretching peak in Raman spectra; however it is very difficult toobserve Raman scattering from such an adsorbed molecule.We further show that WOx enables us to detect even single-molecule through Raman spectroscopy. This result indicatesthat an extremely large enhancement effect of Raman scatter-ing is indeed available with a metal oxide if it is appropriatelyengineered. WOx (x = 2.75) is an atomically well-defined singlecrystal with two-dimensional conducting layers as revealed byour theoretical calculations.2. Results and discussionThe large enhancement effect of Raman scattering thatenables the observation of adsorbed molecule originates fromWOx nanorod. Fig. 1a shows a scanning electron microscope†Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2nr03596kaInternational Center for Materials Nanoarchitectonics (WPI-MANA), NationalInstitute for Materials Science (NIMS), 1-1 Namiki, Tsukuba 305-0044, Japan.E-mail: SHINGAYA.Yoshitaka@nims.go.jp, NAKAYAMA.Tomonobu@nims.go.jpbFaculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai,Tsukuba, Ibaraki 305-8573, JapanThis journal is © The Royal Society of Chemistry 2022 NanoscaleOpen Access Article. Published on 23 September 2022. Downloaded on 10/12/2022 2:33:18 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineView Journalhttp://rsc.li/nanoscalehttp://orcid.org/0000-0002-5926-3302http://orcid.org/0000-0002-8221-009Xhttp://orcid.org/0000-0001-5259-4152http://orcid.org/0000-0002-4058-8967http://orcid.org/0000-0001-9696-475Xhttps://doi.org/10.1039/d2nr03596khttps://doi.org/10.1039/d2nr03596khttps://doi.org/10.1039/d2nr03596khttp://crossmark.crossref.org/dialog/?doi=10.1039/d2nr03596k&domain=pdf&date_stamp=2022-08-26http://creativecommons.org/licenses/by-nc/3.0/http://creativecommons.org/licenses/by-nc/3.0/https://doi.org/10.1039/d2nr03596khttps://pubs.rsc.org/en/journals/journal/NR(SEM) image of WOx nanorods grown on an electrochemicallyetched tungsten tip. The length of the nanorods is typically1–10 µm. The thickness of the WOx nanorods is 20–150 nm, ascan be determined from the SEM image shown in Fig. 1b.Fig. 1c shows a transmission electron microscope image of aWOx nanorod. The nanorod has planar defects of oxygeninside. The periodic stacking of the planar defects forms the{001}-type crystallographic shear (CS) structure described asWnO3n−1. The observed structure corresponds to W4O11, whichis one of the {001}CS structures.34 A structural model ofW4O11-CS is shown in Fig. 1d. Various intermediate oxides oftungsten show metallic conductivity.37–39 However, the electri-cal conductivity of the {001}CS structure remains unclear.Therefore, we carried out the first-principles electronic struc-ture calculation for the W4O11-CS structure on the basis ofdensity functional theory. We obtained the electronic bandstructure by the localized atomic orbital basis set methodimplemented in SAKE.40 We confirmed that the W4O11-CSstructure exhibits a metallic band structure, as shown inFig. 1e. A highly dispersive band that crosses the Fermi energyexists. The band has dispersion in the yz directions, but not inthe x direction. This indicates two-dimensional conductinglayers forming in the {001}CS structure. Our theoretical calcu-lations showed that the wave function of that band localized inthe CS plane as shown in Fig. 1f. It is expected that theplasmon resonance due to free electrons in the two-dimen-sional conducting layers may contribute to the enhancementof Raman scattering.We found that Raman spectra obtained from WOx nanorodscontain Raman scattering attributable to adsorbed molecules,as will be shown later. Therefore, we expected that WOx nano-rods would have the enhancement effect of Raman scattering.Since the peak frequency of an adsorbed molecule largelychanges from position to position, we expect that the numberof observed molecules will be very small and WOx nanorodswill have an extremely large enhancement effect of Ramanscattering. To prove this hypothesis, Raman spectroscopy wascarried out for the WOx nanorods exposed to a 1 : 1 mixture oftwo isotopes. We used adsorbed CO molecules to estimate theenhancement effect. The CO molecules on WOx nanorods wereformed by decomposition of 1 : 1 mixture of methanol-12C andmethanol-13C in an ultra high vacuum (UHV) chamber.41–43Fig. 2a shows accumulated Raman spectra of the adsorbedCO on WOx nanorods formed by the decomposition of metha-nol. The spectra were obtained at 225 different points in a9 µm × 8 µm area on densely grown WOx nanorods, as indi-cated by the square in Fig. 2b. In this area, more than onehundred nanorods were included. Fig. 2b shows an opticalmicroscope image of densely grown WOx nanorods on thetungsten tip. The lower spectrum in Fig. 2a was obtained afterexposing the nanorods to methanol-12C at 600 °C and 5 × 10−5torr for 15 min. Only the peak corresponding to 12CO mole-cules was observed. The upper spectrum of Fig. 2a wasobtained after exposing the nanorods to the 1 : 1 mixture ofmethanol-12C and methanol-13C at 640 °C and 5 × 10−5 torr for10 min. Two peaks correspond to the adsorbed 13CO and 12CO.Since we observed CO molecules on a large number of WOxnanorods in this case, the two peaks appear at a 1 : 1 ratio. Thedifference in vibrational frequency between the two peaks isreasonably attributed to the isotope substitution of the carbonatom of the CO molecules. Normally, it is very difficult toobserve Raman scattering from such adsorbed molecules. Weexpected that the WOx nanorods would have some enhance-ment effect of Raman scattering. Here, we note that as-grownnanorods did not show the Raman peak from CO molecules.After laser irradiation of 1 mW µm−2, CO peaks appeared.Once the peaks corresponding to CO molecules appear in theRaman spectrum, it is possible to observe them even when thelaser intensity is reduced. These results indicate that the acti-vation by laser irradiation is required for detecting adsorbedmolecules.It is necessary to mention here the vibrational frequency ofthe adsorbed CO molecules observed in this study. Thevibrational frequencies of observed CO molecules are muchlower than that of adsorbed CO molecules shown in the pre-Fig. 1 (a) SEM image of WOx nanorods on electrochemically sharpenedtungsten tip. (b) Magnified SEM image of WOx nanorods. (c) TEM imageof WOx nanorod. Observed image corresponds to W4O11 that is inter-mediate oxide of tungsten with {001} type crystallographic shear (CS)structure. (d) Schematic representation of W4O11 structure. Red spheresare oxygen atoms and Green spheres are tungsten atoms. (e) Banddiagram for W4O11-CS structure obtained with density functional theorycalculations. (f ) Wave functions of the band indicated by the arrow.Paper NanoscaleNanoscale This journal is © The Royal Society of Chemistry 2022Open Access Article. Published on 23 September 2022. Downloaded on 10/12/2022 2:33:18 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinehttp://creativecommons.org/licenses/by-nc/3.0/http://creativecommons.org/licenses/by-nc/3.0/https://doi.org/10.1039/d2nr03596kvious SERS measurements.44 This is due to the difference insubstrate materials. What is observed in the literature are COmolecules adsorbed on silver. CO molecules are weaklyadsorbed on silver, therefore the intramolecular bonding ofCO molecules is not very different from that of CO moleculesin the gas phase. In contrast, CO molecules are stronglyadsorbed on transition metals. As a result, the intramolecularbonding of CO become weaker and the intramolecularvibrations shift to lower frequencies. It is known that CO mole-cules adsorbed on the bridge site have a particularly large lowfrequency shift. The 1850 cm−1 obtained in the present studycorresponds well to the peak position of CO moleculesadsorbed on the bridge site of the transition metal surface.45As can be seen from the structural model in Fig. 1d, tungstenoxide nanorods with CS planes have bridge sites on the CSplanes. It is considered that the CO molecules adsorbed on thebridge sites on the CS planes are observed in this study.Fig. 2c shows Raman spectra from an intermediate numberof WOx nanorods. In this case, WOx nanorods were exposed to1 × 10−6 torr methanol for 100 seconds at room temperatureafter growth. To reduce the number of observed molecule, thenumber of accumulated pixels was reduced to 9 in a 2 µm ×2 µm area. In this area, 20–50 nanorods were included. Fourspectra were obtained at different positions on densely grownWOx nanorods, as shown in Fig. 2d with the correspondinglynumbered squares. Although the 1 : 1 mixture of methanol-12Cand methanol-13C was used in this case, the intensity ratio of13CO to 12CO is not anymore 1 : 1. This indicates that thenumber of observed CO molecules was already very small. Theappearance of multiple components in the CO stretchingmode is due to a subtle difference between the adsorptionstates of CO on WOx nanorods46 that are averaged out when weobserve many adsorbed molecules. Several components thatoriginate from different adsorption sites appeared for a smallnumber of adsorbed CO molecules. The intensity ratio differedfrom position to position.To further reduce their number, WOx nanorods were dis-persed on a Si substrate, and Raman spectra were observedfrom 1–3 WOx nanorods. Fig. 2e shows the Raman spectraobtained at the single point indicated by the red circle inFig. 2f. In this case, the intensity ratio of 12CO to 13COincreases further. Almost no 13CO peak appears except for asmall peak at 1783 cm−1, whereas a very sharp and intensepeak at 1848 cm−1 and a smaller peak at 1862 cm−1 appear for12CO. Since the ratio of 12CO to 13CO should be 1 : 1 if theRaman spectra correspond to many molecules, this resultstrongly suggests that single-molecule-level observationbecomes possible for adsorbed CO.To prove the single-molecule Raman scattering observationwith an extremely large enhancement effect of WOx nanorodsmore clearly, Raman mapping was conducted for WOx nano-rods with a 1 : 1 isotope mixture of CO. Fig. 3a and b showoptical microscope and SEM images of WOx nanorods dis-persed on a Si substrate. Fig. 3c and e respectively showRaman mappings of the 13CO and 12CO peaks obtained at thesame area as in Fig. 3a and b. The result of mapping for the13CO peak is totally different from that for the 12CO peak.Fig. 3d and f show the spectra obtained at the positions indi-cated by circles in Fig. 3c and e. We observed that only oneisotope appears in each spectrum. This indicates that theobserved peaks originate from a very small number of COmolecules, that is, the single-molecule-level.As mentioned above, as-grown nanorods did not show alarge enhancement effect of Raman scattering to enablesingle-molecule detection. After laser irradiation as intense as0.1–1.5 mW µm−2, single-molecule detection became possible.The threshold intensities of activation were dependent on theFig. 2 (a) Raman scattering spectra of adsorbed CO on WOx nanorodsformed by decomposition of methanol. The spectra were obtained at225 different points in a 9 µm × 8 µm area on densely grown WOx nano-rods as indicated by the square in (b). More than 100 nanorods arepresent in this region. The lower spectrum was obtained after exposingthe nanorods to methanol-12C at 600 °C and 5 × 10−5 torr for 15 min.The upper spectrum was obtained after exposing the nanorods to the1 : 1 mixture of methanol-12C and methanol-13C at 640 °C and 5 × 10−5torr for 10 min. Raman scattering measurements were carried out in air.(b) Optical microscope image of tungsten tip with densely grown WOxnanorods. (c) Raman spectra of adsorbed CO from 20–50 of WOx nano-rods. (d) Optical microscope image of tungsten tip with densely grownWOx nanorods. The four red squares indicate the observed areas ofRaman spectra in (c). (e) Raman spectra of adsorbed CO from 1–3 ofWOx nanorods on Si substrate. (f ) Optical microscope image of WOxnanorods on Si substrate. Excitation laser: Ar+ laser, 514.5 nm, 1.0 mWfor (a and e) 0.1 mW for (c).Nanoscale PaperThis journal is © The Royal Society of Chemistry 2022 NanoscaleOpen Access Article. Published on 23 September 2022. Downloaded on 10/12/2022 2:33:18 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinehttp://creativecommons.org/licenses/by-nc/3.0/http://creativecommons.org/licenses/by-nc/3.0/https://doi.org/10.1039/d2nr03596kdiameter and position of WOx nanorods. Nanorods with largerdiameters tend to be activated at a lower intensity of an irra-diated laser. In addition, the laser irradiation near the end of ananorod can activate the nanorod of a lower laser power thanthe irradiation in the center of the nanorod. This activationprocedure corresponds to cutting the CS planes by the localoxidation of WOx and localizing the plasmon at the active siteformed by the oxidation.It should be mentioned here that the enhancement factor(EF) become very large, over 1010. The calculation of the EF isdescribed in ESI.† CO molecules do not have absorption in thevisible light region. Therefore, the resonance Raman effect isnot expected. We consider that this very large enhancementfactor is mainly caused by the electromagnetic mechanismdue to plasmon resonance. The results of additional experi-ments supporting this explanation are shown in Fig. S1 and S2in ESI.† The light scattering spectrum obtained from a singleWOx nanorod is shown in Fig. S1.† The light scattering with apeak around 450 nm is attributed to the plasmon resonance ofthe WOx nanorod. When the light within the peak wavelengthregion of the light scattering spectrum is used as the excitationlight for Raman scattering, a large enhancement effect isobtained. Fig. S2† shows the results of electrical measure-ments of a single tungsten oxide nanorod using the prober inthe SEM. A completely linear IV curves were obtained, indicat-ing that the WOx nanorods have metallic electrical properties.The electrical resistivity determined from the diameter and thelength of the nanorod was quite low, 2.9 × 10−4 Ω cm. Theseresults support electromagnetic mechanism due to plasmonresonance. There is possibility that charge transfer mechanismalso contribute to the large enhancement effect. The details ofthe enhancement mechanism are not yet clear, and are con-sidered to be a target for future work.The enhanced Raman scattering of adsorbed CO on WOxnanorods shows time-dependent spectral changes, that is, theso-called blinking phenomenon. As the blinking is character-istic of single-molecule observation,9,47–49 the following resultis additional evidence that the observed CO is at the single-molecule level. Fig. 4a shows time series Raman spectra ofadsorbed CO on WOx nanorods dispersed on the Si substrateacquired at 1.5 s intervals. In this case also, 13CO and 12COexist at a 1 : 1 ratio on WOx nanorods. Fig. 4b indicates theRaman spectra obtained at various times. A peak at 1772 cm−1corresponds to 13CO molecule and peaks at 1855 and1886 cm−1 correspond to 12CO molecules. The large differencein peak intensity between 13CO and 12CO indicates that thenumber of observed CO molecules is very small (single-mole-cule level). The peak at 1772 cm−1 comes from single 13COmolecule, and it shows time-dependent changes in its inten-sity and position. These time-dependent changes are due tochange of adsorption site of CO. At t = 48.5 s an intense peakappears at 1745 cm−1. The peak rapidly disappears because ofthe instability of the adsorption state that causes a rather lowvibrational frequency of CO. After this event, a shoulder peakappears at 1795 cm−1. Fig. 4c shows plots of peak intensitiesFig. 3 (a) Optical microscope image and (b) scanning electron micro-scope image of WOx nanorods on Si substrate. Raman mappings of (c)13CO and (e) 12CO measured in the same area as in (a and b). (d and f)Show Raman spectra obtained at the positions indicated by circles in (cand e). Excitation laser: Ar+ laser, 514.5 nm, 1.0 mW.Fig. 4 (a) Time series Raman spectra of adsorbed CO on WOx nanorodsdispersed on Si substrate acquired at 1.5 s intervals. (b) Raman spectraobtained at t = 0, 48.5, 50 and 144 s. (c) Peak intensity plots as a func-tion of time. Excitation laser: Ar+ laser, 514.5 nm, 1.0 mW.Paper NanoscaleNanoscale This journal is © The Royal Society of Chemistry 2022Open Access Article. Published on 23 September 2022. Downloaded on 10/12/2022 2:33:18 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinehttp://creativecommons.org/licenses/by-nc/3.0/http://creativecommons.org/licenses/by-nc/3.0/https://doi.org/10.1039/d2nr03596kas a function of time. The peak intensities of each peak wereobtained by peak fitting. Although the peak intensities of 12COat 1855 and 1886 cm−1 were constant throughout the measure-ments, the peak intensity of 13CO at 1772 cm−1 drasticallychanged. The splitting of the peak starting at t = 48.5 s corres-ponds to the rapid hopping of CO molecule between twoadsorption states. The peak intensity indicates the occupationtime of each adsorption state. The peak intensity at 1772 cm−1gradually decreases from t = 124 s, whereas the peak intensityat 1795 cm−1 increases. The total intensity of peaks at1772 cm−1 and 1795 cm−1 was almost constant after the startof splitting at t = 48.5 s. This result clearly indicates the nega-tive correlation between two peaks and can be explained by thevariation of the occupation time between two different adsorp-tion states. When we observe thousands of molecules using aconventional spectroscopic technique, such detailed infor-mation of adsorption states is averaged out. Single-moleculedetection with a large enhancement effect of Raman scatteringenables us to examine in detail the dynamic behavior of thebonding state and environmental conditions of the targetmolecule.3. ConclusionsWe have found that WOx nanorods show an extremely largeenhancement effect of Raman scattering, and the vibrationalspectra of a single adsorbed CO molecule become observable.Although as-grown nanorods did not show a large enhance-ment effect of Raman scattering, after laser irradiation at anintensity of 0.1–1.5 mW µm−2, single-molecule detectionbecame possible. This activation procedure corresponds tocutting the CS planes by the local oxidation of WOx, and thelocally oxidized part works as the active site for Ramanenhancement. The Raman mapping of the isotope mixtureproved the detection of a single molecule. The Ramanmapping was performed for nanorods with adsorbed 12CO and13CO at the ratio of 1 : 1. The Raman images of 12CO and 13COwere completely different, indicating that a very small numberof molecules at the single-molecule level were observed. DFTcalculations revealed the existence of a 2D conducting layer atthe CS plane. Therefore, we considered that plasmon reso-nance using free electrons in 2D conducting layers in WOxnanorods is the main factor for the large enhancement effect.Conventional single-molecule SERS is always realized in anearly closed system such as a nanogap or nanocavity. In con-trast, the enhancement of Raman scattering by WOx isexpected to be realized at the cleavage site of conductingplanes at the surfaces of nanorods. It is considered that theactive sites of Raman enhancement can be brought into closeproximity to macromolecules such as proteins. Therefore, thistechnique has the potential to greatly expand the applicationof single-molecule SERS. WOx nanorods can be attached to theapex of probe for a scanning probe microscope.50 Therefore,chemical analysis with extremely high spatial resolution isexpected to realize.4. Experimental sectionWe have already developed an epitaxial growth technique forWOx nanorods on tungsten in a UHV chamber.50–52 The WOxnanorods were grown on electrochemically etched tungstensubstrates. The substrates were annealed at 1100 °C to removethe residual oxide layer on the surface. Then the substrate waskept at 700 °C to 850 °C. Oxygen gas at 5 × 10−6 torr was intro-duced into the chamber, and the tungsten foil heated at1100 °C was placed in front of the substrate in order to deposittungsten oxide on the substrate. The growth time was 5 to10 h. The obtained tungsten oxide showed a nanorod shape.Raman scattering spectral measurements were performed in airwith a micro-Raman system (HORIBA Jobin-Yvon, HR-800) usingan Ar-ion laser of 514.5 nm wavelength for excitation focused in a1 µm diameter spot with a 100× objective lens (Olympus, 0.90numerical aperture). The light that scattered back from the samplewas collected with the same objective lens and detected through apolychromator with a liquid-nitrogen-cooled CCD camera. Detailedstructures of WOx nanorods were observed by field emission-SEM(JEOL JSM-6500F) and TEM (JEOL JEM-2000EX). Highly pureoxygen gas (99.99995%) was used for WOx nanorod growth.Deuterated methanol-12C,13C (Cambridge Isotope Laboratories)was used for the formation of adsorbed molecules.Author contributionsThe manuscript was written by Y. S. and T. N. through thesupport of all the co-authors. Y. S. performed growth andcharacterization of WOx nanorods. Y. S. performed micro-Raman measurements. H. T. and N. K. performed theoreticalcalculations. N. K. and M. A. discussed band structure andpossible enhancement mechanism. All the authors analyzedthe data, discussed the results and commented on themanuscript.Conflicts of interestThe authors declare no conflicts of interest.AcknowledgementsWe would like to thank Dr K. Kurashima for TEM observation.This study was supported by the World Premier InternationalCenter (WPI) for Materials Nanoarchitectonics (MANA) of theNational Institute for Materials Science (NIMS), Tsukuba,Japan, and JSPS Kakenhi grant number 20K05280.References1 S. Schlucker, Angew. Chem., Int. Ed., 2014, 53, 4756–4795.2 E. C. Le Ru and P. G. Etchegoin, Annu. Rev. Phys. Chem.,2012, 63, 65–87.Nanoscale PaperThis journal is © The Royal Society of Chemistry 2022 NanoscaleOpen Access Article. Published on 23 September 2022. Downloaded on 10/12/2022 2:33:18 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinehttp://creativecommons.org/licenses/by-nc/3.0/http://creativecommons.org/licenses/by-nc/3.0/https://doi.org/10.1039/d2nr03596k3 M. Mascini and S. Tombelli, Biomarkers, 2008, 13, 637–657.4 C. I. L. Justino, A. C. Duarte and T. A. P. Rocha-Santos,Sensors, 2017, 17, 2918–2943.5 Z. Lin and L. He, Curr. Opin. 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