Plasmonic and chiroplasmonic nanobiosensors based on gold nanoparticles

Journal Pre-proof Plasmonic and chiroplasmonic nanobiosensors based on gold nanoparticles Majid Sharifi, Sara Haji Hosseinali, Reza Hossein Alizadeh, Anwarul Hasan, Farnoosh Attar, Abbas Salihi, Mudhir Sabir Shekha, Karwan M. Amen, Falah Mohammad Aziz, Ali Akbar Saboury, Keivan Akhtari, Akbar Taghizadeh, Nasrin Hooshmand, Mostafa A. El-Sayed, Mojtaba Falahati PII:

S0039-9140(20)30073-4

DOI:

https://doi.org/10.1016/j.talanta.2020.120782

Reference:

TAL 120782

To appear in:

Talanta

Received Date: 7 November 2019 Revised Date:

23 January 2020

Accepted Date: 24 January 2020

Please cite this article as: M. Sharifi, S.H. Hosseinali, R.H. Alizadeh, A. Hasan, F. Attar, A. Salihi, M.S. Shekha, K.M. Amen, F.M. Aziz, A.A. Saboury, K. Akhtari, A. Taghizadeh, N. Hooshmand, M.A. El-Sayed, M. Falahati, Plasmonic and chiroplasmonic nanobiosensors based on gold nanoparticles, Talanta (2020), doi: https://doi.org/10.1016/j.talanta.2020.120782. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

Plasmonic and chiroplasmonic nanobiosensors based on gold nanoparticles

Majid Sharifi1,2, Sara Haji Hosseinali3, Reza Hossein Alizadeh1, Anwarul Hasan4,5*, Farnoosh Attar6, Abbas Salihi7,8, Mudhir Sabir Shekha7,9, Karwan M. Amen8,10, Falah Mohammad Aziz7, Ali Akbar Saboury11, Keivan Akhtari12, Akbar Taghizadeh2, Nasrin Hooshmand13, Mostafa A. El-Sayed13,*, Mojtaba Falahati1*

1

Department of Nanotechnology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 2 Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran. 3 Department of Genetics, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran 4 Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha 2713, Qatar. 5 Biomedical Research Center, Qatar University, Doha 2713, Qatar. 6 Department of Biology, Faculty of Food Industry & Agriculture, Standard Research Institute (SRI), Karaj, Iran. 7 Department of Biology, College of Science, Salahaddin University-Erbil, Kurdistan Region, Iraq. 8 Department of Medical Analysis, Faculty of Science, Tishk International University, Erbil, Iraq. 9 Department of Medical Laboratory Science, Knowledge University, Erbil, Iraq. 10 College of Nursing, Hawler Medical University, Erbil, Iraq. 11 Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. 12 Department of Physics, University of Kurdistan, Sanandaj, Iran. 13 Laser Dynamics Laboratory, School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, United States.

*Corresponding authors: Mojtaba Falahati: [email protected] Mostafa El-Sayed: [email protected] Anwarul Hasan: [email protected]

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ABSTRACT Development of optical nanobiosensors is one of the important priorities especially in the field of biomedical diagnostics science and technology. The application of nanobiosensors has been accelerated with the introduction of plasmonic NPs, which overcome the most of the limitations in the case of conventional optical nanobiosensors. Since the plasmonic AuNPsbased nanobiosensors provide high potential achievements to develop promising platforms in fully integrated multiplex assays, some well-developed investigations are clearly required to improve the current technologies and integration of multiple signal inputs. Therefore, in this literature, we summarized the performance and achievements of optical nanobiosensors according to plasmonic rules of AuNPs, including SPR, LSPR, SERS and chiroptical phenomena. Also, we investigated the effects of the physicochemical properties of AuNPs such as size, shape, composition, and assembly on the plasmonic signal propagation in AuNPs-based nanobiosensors. Moreover, we presented an overview on the current state of plasmonic AuNPs-based nanobiosensors in the biomedical activities. Besides, this paper looks at the current and future challenges and opportunities of ongoing efforts to achieve the potential applications of AuNPs-based optical plasmonic nanobiosensors in integration with other nanomaterials. Taken together, the main focus of this paper is to provide some applicable information to develop current methodologies in fabrication of potential AuNPsbased nanobiosensors for detection of a wide range of analytes.

Keywords: Plasmonic AuNPs; SPR; LSPR; SERS; Chiroptical; Analyte, detection.

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Contents 1. Introduction .............................................................................................................. 4 1.1. AuNPs importance in plasmonics ......................................................................... 5 1.2. The aims and structure of review .......................................................................... 5 2. Fabrication of plasmonic AuNPs for biosensing ........................................................... 6 2.1. Plasmonic gold nanospheres ................................................................................. 6 2.2. Plasmonic gold nanorods ..................................................................................... 8 2.3. Plasmonic gold nanoshells ................................................................................... 9 2.4. Plasmonic gold nanocages ................................................................................. 10 3. Factors influencing plasmonic properties of AuNPs .................................................... 11 3.1. Dielectric environment ...................................................................................... 11 3.2. Size ................................................................................................................. 12 3.3. Shape............................................................................................................... 13 3.4. Composition ..................................................................................................... 13 3.5. Assembly of AuNPs .......................................................................................... 14 3.6. Physicochemical properties ................................................................................ 15 4. SPR biosensors based on plasmonic AuNPs ............................................................... 15 4.1. Principals of SPR biosensors .............................................................................. 16 4.2. Applications of SPR nanobiosensors ................................................................... 17 4.2.1. SPR nanobiosensors for cancers detection ..................................................... 17 4.2.2. SPR nanobiosensors for high-throughput screening ........................................ 18 5. LSPR nanobiosensors based on plasmonic AuNPs ...................................................... 19 5.1. Principals of LSPR biosensors ............................................................................ 19 5.2. Optical fiber-based LSPR nanobiosensors ........................................................... 21 5.3. Chip-based LSPR nanobiosensors ....................................................................... 23 5.4. Solution phase-based LSPR nanobiosensors ........................................................ 25 5.5. Comparison among of SPR and LSPR nanobiosensors .......................................... 26 6. SERS nanobiosensors based on plasmonic AuNPs ...................................................... 26 6.1. Principals of SERS nanobiosensors ..................................................................... 27 6.1.1. SERS nanobiosensors based on single plasmonic AuNPs ................................ 28 6.1.2. SERS nanobiosensors based on plasmonic assemblies of AuNPs ..................... 29 6.2. Application of SERS nanobiosensors based on plasmonic AuNPs .......................... 30 7. Chiroptical nanobiosensors based on plasmonic AuNPs .............................................. 32 7.1. Chiroptical effects ............................................................................................. 32 7.2. Enhancement of chiroptical effects ..................................................................... 34 7.3. Intrinsic effects of chiroptical in AuNPs .............................................................. 35 7.4. Synthesis and application of chiroplasmonic AuNPs ............................................. 35 7.4.1 Synthesis .................................................................................................... 35 7.4.2. Application ................................................................................................ 36 8. Conclusion and outlook ........................................................................................... 38 Conflicts of interest ..................................................................................................... 40 Acknowledgment ........................................................................................................ 40 References ................................................................................................................. 40

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1. Introduction A plasmon is a physical event that determines the plasma oscillations. Therefore, the plasmon is a quasi-particle caused by the plural oscillations of free electrons, which is due to the variation of optical frequencies [1]. While, in surface plasmons, instead of considering the free electron oscillations, the collective oscillation of conduction electrons in a metal have been studied. As a result, surface plasmons are limited to surfaces that interact with light and lead to surface plasmonic wave [2]. Plasmonics, which describes the cooperative mobility of electrons in metals, allows the connection of light with nanoscale objects and the production of a range of new optical effects. Surface plasmons states can be classified into two groups: propagating surface plasmons (PSP) and localized surface plasmons (LSP). PSP has been used in many biosensing/biorecognition applications, which include superficial

electromagnetic waves

supported

on

a metal/dielectric interface [3].

Electromagnetic waves are coherently conjugated with the plural action of moving charges at the metal surface, which results in high rates of PSP frequency [4]. Therefore, the excitation of PSP needs some sort of acceleration matching procedure such as prism and grating coupling. PSP is very sensitive to minor changes in the depth of the shells, and for this reason, PSP is often used to check the surface mismatch [5]. Indeed, surface plasmon polariton (SPPs) provide a label-free technology to recognize and study biomolecular combining incidents with a target analyte and its corresponding receptor immobilized on the metal interface [4]. The LSP is due to the surface plasmon confinement in nanoparticles (NPs) with a size smaller or equal to the wavelength of incident light. They have two very important effects, including electrical fields near particle surfaces and particle's optical absorption [2]. However, the LSPs oscillations depends drastically on the composition, geometry, size, dielectric environment and the particle-particle separation distance in nanomaterials [6]. The

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LSPs have been used as a convenient substitute for PSP in a wide range of medical applications that do not have PSP problems such as the acceleration matching techniques for exciting and complex fabricating routes [7]. Other benefits of using LPSs in comparison to PSP, include the ability of manipulate light at the nanoscale level, supersensitive plasmonic nanosensors, and active optical elements [8, 9].

1.1. AuNPs importance in plasmonics In recent decades, the use of plasmonic gold nanoparticles (AuNPs) in medical activities such as biosensing, imaging and therapeutic has been widely received a great attention due to the displaying high chemical and physical stability, high biocompatibility, high performance in the face of organic and biological molecules, and highly desirable optical properties [8, 10]. In fact, AuNPs >2 nm in comparison with other compounds because of their higher extinction cross-section provide a high ability to convert light to heat, electromagnetic field amplification, and high photostability [10, 11]. However, the plasmonic activities of AuNPs, which are reliant on two principal factors, the intrinsic properties of the AuNPs and the environmental features [12], must be constantly addressed in standard electromagnetic methods along with quantum effects.

1.2. The aims and structure of review Despite significant advances in the production of plasmonic AuNPs nanobiosensors, this section has not been well-summarized in the medical field. Therefore, as a first objective, this review attempts to investigate different aspects of plasmonic AuNPs in the field of medical nanobio- or nano-sensors. Then, by analysing the reports presented, it examines how to reduce the challenges of plasmonic AuNPs nanobiosensors in the medical field, and provide a clear picture of controlling the active AuNP plasmonic structures. Thus, this

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literature was classified into eight major parts. In section 1, we discussed the different types of plasmonics, the importance of AuNPs in plasmonic field, and the facts or open questions in this field. In section 2, we briefly described the methods for synthesizing AuNPs and their plasmonic properties. Section 3 referred to the effect of the physicochemical properties of AuNPs on the plasmonic phenomenon. Then, in section 4, 5 and 6, we pointed out the importance of using the plasmonic properties of AuNPs in surface plasmon resonance (SPR), localized surface plasmon resonance (LSPR) and surface enhance Raman scattering (SERS) biosensing. The outstanding achievement of chiroptical sensing applications is highlighted in section 7. Ultimately, in section 8 we attempted to clarify the applications of plasmonic AuNPs biosensors in the biomedical field.

2. Fabrication of plasmonic AuNPs for biosensing Reliable and accurate manufacturing methods of AuNPs are required to achieve successful advancement in plasmonic activities of AuNPs. Despite the cost-effective and simple chemical synthesis, AuNPs are produced by various techniques, including different types of lithography, biosynthetic organisms, etc. with differing sizes and morphologies [12, 13].

2.1. Plasmonic gold nanospheres One of the most widely designed AuNPs is spherical or polygonal shapes with the highest stability and the smallest surface-to-volume ratio. Despite the various processes for synthesis of Au nanospheres (AuNSPs) such as polymer-mediated synthesis, UV-induced photochemical synthesis, ultrasound-assisted synthesis, laser ablation synthesis, bio-inspired procedures, and green-based method, the most widely applied route for synthesizing AuNSPs with an average size of 15 nm was provided by Turkevitch and developed by Frens [14],

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which are produced through reducing the HAuCl4 compound by sodium citrate. In this regard, sodium citrate acts as both reducing and stabilizing agent for Au anion. This means that changes in the concentration of citrate can vary the size of fabricated NPs between 15 and 150 nm. Photophysical responses of AuNSPs based on the color and heat interpreted that both of them are measured by absorption (Cabs) and scattering (Csca) cross-section (equation 1) [15]. Despite the existence of various optical hypotheses, the application of Mie's theory has more application for each type and size of NPs [16]. In this theory, with the determination of the cross-sectional area and the light exposure, a bipolar oscillation occurs. According to Mie equations 1, 2 and 3, the nature of the NP, the particle size, shape, structure, composition, and environment dielectric constant are effective on oscillation. Equation 1:

Csca = Cext – Cabs

3 2 24 2 3     + 2 2 + 2  −  = 4 3 Im    + 2

Equation 2:
 = Equation 3:


⁄

In equation 2, Cext is the extinction cross-section, λ is the wavelength of the light, εm is the dielectric constant of environment, ε=εr+iεi is the complex dielectric constant of the particle, which the real part of dielectric constant (εr) determines the SPR position, the imagery part (εi) determines the bandwidth and k is the wave vector of light in the media (k = 2π/λ). In this regard, a peak of resonance is observed at a time of εr=-2εm. According to the idea, the maximum LSPR peaks of 5 and 70 nm AuNSPs are appeared at 520 and 530 nm, respectively. Thus, raising the size of AuNSPs augments the power of Csca relative to Cabs. Nevertheless, it is impossible to set up the LSPR peak for the AuNSPs in the range of 700−900 nm for a diameters of less than 100 nm [17]. These ranges could be controlled by altering the constant dielectric environment (solvent). Therefore, the peak position and the

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resonance bandwidth generated depend on the size and shape of the AuNSPs and the dielectric constant of environment.

2.2. Plasmonic gold nanorods Although the gold nanorods (AuNRs) fabrication methods are somewhat similar to those of AuNSP, fabricating AuNR is a bit more complicated. Among the various methods such as template, electron beam lithography, seedless, photochemical, and electrochemical, the application of seed growth is considered as the easiest and most potential route. In a twoor three-step seed growth protocol, first, HAuCl4 along with sodium borohydride and in the presence of sodium citrate forms NSPs. Then, the AuNSPs begin to grow on the surface of the seeds, containing HAuCl4, cetyl-trimethyl ammonium bromide (CTAB, as the template), ascorbic acid (reducing agent) and silver (Ag) nitrate (modulation of shape) to allow the growth of AuNRs [18]. In elliptic AuNRs with dipole approximation, according to Gans's hypothesis, the surface plasmon state is divided into two strong and weak bonds. A strong bond in the position of near-infrared region (NIR) related to the electron oscillation in the longitudinal axis of the AuNR, and a weak band at wavelength similar to the NPs showing the electron oscillation in the transverse axis [16]. Based on Gans's equations, the cross-section of the AuNRs is calculated using the following equation 4. Equation 4:




3 2 2 = 3 ⁄



1⁄"#2 

2

$ + $1 − "# %&"#  % + 2

In this equation V is volume of the AuNRs, Pj is the depolarization factor which may be described as equation 5 and 6: Equation 5: Equation 6:

"'() ℎ

"/0 ℎ

1 − 2 1 1+ = ln . − 1  2 2 1− 1 − "'() ℎ = 2

8

Where e2 is the ellipticity (equation 7): Equation 7:

2 = 1 − -

'()ℎ −2 . /0ℎ

Based on equation 4, it can be noted that the LSPR occurs when εr is equal to −((1−Pj)/Pj)εm. While, the linear relationship of longitudinal SPR maximum absorption with the ratio of length-to-width (which the SPR maximum is linearly red shifted) can be observed in the following equation 8 [19]: Equation 8: λmax = 95 R + 420. Also, the equation 4 shows that any small variation in the length-to-width ratio results in a significant changes in the plasmonic activity of AuNPs, like the color changes from blue to red.

2.3. Plasmonic gold nanoshells The first gold nanoshells (AuNSs) with SPR peaks in the NIR was synthesized by Oldenburg, et al. [20]. The most important method applied to create AuNS is the seed formation and growth route, which the silica (SiO2) along with polystyrene cores with terminal amine groups is used [21]. However, it has been shown that the application of polystyrene rather than SiO2is more suitable because of the higher degree of uniformity and increased pixar resonance absorption occurs due to the high refractive index (RI) between the shell and core [22]. The plasmonic properties of AuNSs represent a collective oscillation of free electrons, which plasmonic extinction is expanded with increasing the diameter of the shell. Indeed, by reducing the shell-to-core ratio, SPR can be changed from visible to IR region [23]. Because the electron release pathway in AuNSs is much denser than the AuNSPs, it is very important to properly describe the dielectric performance due to the electron surface dispersion. Different approaches based on Mie's model are presented to study the variation of surface

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resonance imprint, which the most important of them is a Drude-Lorentz model [24]. The dielectric function, ɛ(ω), of a AuNPs is determined by two components (equation 9); The Drude free-electron component, ɛDrude(ω), and the inter-band transition component, ɛinter(ω), which the latter is related to transitions from d level to the states above the Fermi level. Equation 9: ɛ(ω) = ɛDrude(ω) +ɛinter(ω) Mathematically, the Drude-Lorentz dielectric function is given as following (equation 10): Equation 10: :;0 −<3(= 7 = >1 −

7?2 A + <7 7 2 + @7

Where ω is the angular frequency of the electromagnetic field, ωp is the volume plasma frequency of bulk Au, and B is the bulk collision frequency. The second part of the equation 10 (L(ω)) is equal to the transfer between the bands. For measurement of the scattering (equation 11), absorption (equation 12), and extinction cross-sections (equation 13) are used:

8 2 74 |17|2 32 4 27Im17 Equation 12: 6 7 = 2

Equation 11: 62 7 =

Equation 13: 6 7 = 6 7 − 62 7 Where c is the speed of light and α is the polarizability index (equation 14):

ℎ'' −  23 − 2ℎ''  + 4 23 − ℎ''  − 2ℎ''  ℎ'' + 2 23 + 2ℎ''  + 4 2ℎ'' − 2 23 − ℎ'' 

2 Equation 14: 1 = 4ℎ'' 

F the percentage of core volume calculated by equation 15 as following: 1/3 Equation 15: 4 = $23 &ℎ'' %

2.4. Plasmonic gold nanocages To fabricate gold nanocages (AuNCs), a two-step route is used including a polyol reduction followed by the galvanic embedment reaction between Ag and Au via creating an electrochemical potential difference [25]. Concerning the preparation of AuNCs, the redox potential of AuCl4-/Au (0.99 V vs SHE) is more positive than that of AgCl/Ag (0.22 V vs

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SHE). So, the AgNCs acts as a template for oxidizing Au salts to produce AuNCs based on the following reaction [26]: 3Ag(s) + HAuCl4 → Au(s) + 3AgCl(s) + HCl(aq) By controlling the galvanic replacement stage, different peaks of SPR are obtained depending on the variation of the thickness of the walls. Therefore, by adjusting the cross-sectional area of absorption based on the particle size, edge length and wall deep, they can potentially be used for medical biosensing and imaging [27]. The equations of absorption (equation 16), scattering (equation 17) and extinction cross-sections (equation 18) of an AuNC in Comsol Multiphysics are outlined as following: 1 N QdV E0 1 = GH. Jsca dV E0

Equation 16:
abs = Equation 17: Equation 18:


sca


ext =
abs +
sca

Where Q is the energy waste density in the particle, I0 is the event severity, n defines the normal vector pointing outwards from the material surface, and Ssca shows the pointing vector. It should be noted that AuNCs similar to AuNRs have a much higher absorption and dispersion than AuNSs and AuNSPs [28].

3. Factors influencing plasmonic properties of AuNPs 3.1. Dielectric environment The εm value can be changed according to a variety of factors such as altering the density of the environment, absorbing and non-absorbing environment, the presence of organic or inorganic shells, types of ligands, and chemical compounds on the NP. The variation of εm results in the variation of the SPR frequency of the metal NPs. For instance, increasing the εm from water to glass causes the SPR frequency tendency to the red zone, and decreasing εm from water to air, changes the SPR frequency to the blue zone [9]. Based on the

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non-absorbing properties of the dielectric environment, Caldarola, et al. [29] and de Sousa, et al. [30] using SiO2 NPs in the matrix with decreasing εm, were able to avoid the focus of light in certain fields due to the non-absorbing dielectric environment to create hot spots, which is abundantly found in metal matrix. In this way, not only the level of light-to-heat conversion at the matrix surface was reduced (75%) compared to Au nano-antennas (18 times less than the points containing AuNPs), but also surface enhanced fluorescence (SEF) and SRES increased up to 103 times. Also, Talebi Moghaddam, et al. [31] by applying SiO2 as the matrix of AuNPs, were able to provide more accurate images of the distances between AuNPs by AFM tip due to the nature of the non-absorbing dielectric matrix. Analogously, it was determined that the absorption spectrum of the SPR of nanohybrids resulted from AuNPs and aluminum dioxide matrix on glass substrate have tendency to the blue zone with a range of 590 to 631 nm [32].

3.2. Size The Drude free-electron component is mostly affected by the size of the AuNPs. Kolwas and Derkachova [33] determined the dependence of SPR parameters for a broad range of particle radii and plasmon polarities. They derived the dependence of the SPR frequencies and damping rates of surface plasmons on the particle radius. On the other hand, the LSPR of the AuNPs is varied by changing the size of NPs, which increases the intensity of the dark field scattering [34, 35]. Whereas, the intensity of SERS increases with a reduction in the size of AuNPs, due to the stronger effect of lightning rod and weakening of radiation damping [36]. However, the severity of SERS increases with reducing the particle size when the spectral stimulation wavelength is close to the LSPR wavelength. On the whole, in an AuNPs with a size of d<λ, the absorption prevails over scattering [37]. Meanwhile, scattering and absorption efficiencies of NPs smaller than λ are correlated with

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the 6th and 3rd power of the particle size, respectively [38]. Hence, scattering and absorbtion are simultaneously occured in the case of AuNPs with a size of about 50 nm, and the scattering prevails over absorption in the case of AuNPs with the size of 70 to 100 nm [39, 40].

3.3. Shape The LSPR could be simply regulated by altering the shape of the NPs, because sharp features enhance the electrical field [41]. Changing the morphology of NPs is an effective way to change the location, quantity and severity of SPR. This property changes the energy level of NPs in various forms [38]. For instance, AuNSPs of size 2-50 nm show only one SPR band in the range of 520 nm, while when the morphology of AuNPs changes from spherical shape to rod-shaped NPs, two SPR bands are detected [42]. Also, Notarianni, et al. [43] stated that, at the same size (40 nm), with the variation of the morphology of AuNPs from spherical to hemispherical shape, the rate of absorption increases, contrary to the reduction in scattering.

3.4. Composition SPR is strongly affected by composition of Au alloys and anisotropic metal nanostructures [44]. In alloys Au–Ag NPs, the SPR modulation and latitude modifies linearly from the Ag to the Au values as the stoichiometry is different [45]. For instance, Verbruggen, et al. [46] employed the Au–Ag alloy NPs (Aux Ag1−x) with different fraction of two metals in order to increase the visible light response of Titanium dioxide (TiO2) photocatalysts. Zhu, et al. [47] synthesized anisotropic alloy based on Au nanobipyramids decorated by palladium (Pd) NPs and investigated the effect of deposition of Pd on Au nanobipyramids in plasmonic and photocatalytic behaviors. They showed that the deposition of PdNPs at the ends of the Au

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nanobipyramids can lead to the enhancement of local electric fields at the ends of the alloy and the efficient generation of hot charge carriers, which are potent for injection to the lowest unoccupied molecular orbital of organic compounds and driving chemical reactions. In this regard, Canet-Ferrer, et al. [48] and Dasri and Chingsungnoen [49] showed that the highest wavelength absorption by Au@Fe3O4 NPs occurs at 700 nm, when the thickness of Au in the shell is 1 nm.

3.5. Assembly of AuNPs Plasmons on different NPs and even among NPs from a substance can mutually impress each other based on particle interval, geometry, and relative light polarization. For instance, a trimmer NPs designed with the triangular shape supports several states of dipolar plasmon, including 1) a bonding mode, 2) a non-bonding mode with less energy, and 3) nonbonding modes with higher energy [50]. Linear and 2D arrangements of AuNPs provide new properties of the assembly systems due to plasmonic coupling in the collection [51]. In this regard, Mangold, et al. [52] designed a 2D array of AuNPs on a Si/SiO2 chip by using alcantholic bonding, which increased the photoconductance of the 2D assortments at the plasmon modulation of the surface plasmon of the NPs. It was shown that Cucubit[n] aggregates AuNPs, forming a precise interparticle distance of 0.9 nm, enabling better chemical identification of analyte molecules by optimize SERS [53]. Based on the effect of orientation and distance between AuNRs on their plasmonic properties, Chen, et al. [54] and Zhang, et al. [55] using DNA origami nanobreadboard, were able to reduce the gap between NPs from 26 to 6.1 nm with the highest fluorescence efficiency. Similarly, Yang, et al. [56] with the assembly of AuNSPs on poly(perylene diimide) and poly(ethylene glycol, in addition to increasing the magnetic field capacity, resulted in biosensing and photoacoustic imaging improvement. Two-

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dimensional colloidal supercrystals with regular square arrays derived from AuNSPs assembled on polydimethylsiloxane molds, not only enhanced the plasmonic resonances compared to AuNPs, but also caused the tailoring the optical response of both the nano- and the macroscale [57].

3.6. Physicochemical properties Incorporation of AuNPs in semiconductor matrices influences several aspects of their physiochemical properties. The decline of the surface plasmons in the AuNPs leads to the injection of electrons (hot electrons) into the conduction band of the semiconductor with a hole in the AuNPs [58]. The intimate contact between AuNPs and semiconductor matrices causes the Fermi level equilibration at the interface, which reduces the electron-hole recombination as a key factor in the effectiveness of a the photocatalytic efficiency of a NPs [59]. The role of AuNPs in facilitating physicochemical reactions is not restricted to photo catalytic reactions in visible light [35].

4. SPR biosensors based on plasmonic AuNPs As discussed, the SPR phenomenon occurs between a conductive material and a dielectric medium. This event was first expressed by Wood [60], who in 1941, Fano theoretically interpreted Wood's theory by examining surface wave behaviour [61]. The first SPR sensor was invented by Liedberg for gas and antibody-antigen sensing [62], based on Kershman's prism proposal in 1968. The SPR nanobiosensors are a very potent tool for evaluating various biological and chemical molecules in real time that can measure the variation of refractive index (RI) [63]. Changes in the RI cause a variation in the surface plasmon constant propagation and eventually altering the features of the light wave in the surface plasmon. However, the early SPR biosensors had many challenges because of the low

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molecular weight or the excessive dilution of biological analytes such as antigens or toxins that were highly modified by the use of plasmonic NPs specially Au or Ag NPs in the form of substrate materials and amplification tags [64].

4.1. Principals of SPR biosensors The activity of the SPR biosensors is generally classified based on angular frequency, wavelength, intensity, and phase. However, in general, they all use the same principles in identifying biomaterials. The first parameter is the biosensor response, which is a function of the variation of the RI. On the other hand, the variation of RI depends on the biomaterials concentration and the molecule characteristics. According to equation 19 [7], the biosensor response is proportional to the thickness of the thin layer of the biosensor (h) and the variation of the RI:

0( Γ . 02 ℎ

Equation 19: ∆( = -

Here (dn/dc) and Γ are the biomaterial RI and the surface concentration in area, respectively. The next parameter is the biosensor's sensitivity (equation 20) to an analyte, which depends on the resonant angle or the wavelength output of the biosensor and the RI or its conversion efficiency [65]. Equation 20: URI =

WX W(ef W(ef W(d

Another important parameter is the resolution of the SPR biosensors, which affects the performance characteristics of the limit of detection (LOD) of the biosensor. The resolution of a SPR biosensor is essentially the smallest change in the volume RI sensing that can be detected in the biosensor output (equation 21) [63]. Equation 21:

RI =

6so URI

Here, σso is defined generally based on the standard deviation of noise of the biosensor output.

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4.2. Applications of SPR nanobiosensors SPR nanobiosensors have been used in many fields such as medical diagnosis and monitoring pollution in food and environmental samples. Since the rapid, accurate, and simultaneous detection of molecules or biomarkers has been achieved by using SPR nanobiosensors, the application of this method is increasingly employed to detect a number of analytes.

4.2.1. SPR nanobiosensors for cancers detection In 2016, Erturk et al. were able to increase the LOD of prognostic factors in prostate cancer from 0.1–50 ng mL-1 to 91 pg mL-1 (18×10−14 M) in standard solution using SPR chip designed from Au nanofilms containing prostate specific antigen (PSA), methacrylic acid as functional monomer and ethylene glycol. Also, the selectivity performance of nanobiosensor in serum was determined to be 98% in the presence of albumin and lysozyme as the competitive agents [66]. In the same vein, Yang, et al. [67] with the design of SPR nanobiosensors based on AuNPs modified with cancer prognostic microRNA like miRNA122, in addition to increasing the detection speed of biomarkers for up to 30 min based on changes of wavelength and RI, increased the LOD to 60 fM along with multivariate measurements (Fig. 1A). In this trial, it was shown that the miRNA-122 can be reliably observed and measured in high background of non-targeted miRNA [67]. It was also determined that SPR nanobiosensors based on AuNPs modified with antibody against carcinoembryonic antigen enhanced the LOD of cancerous cells up to 12 and 40 pg mL-1 in buffer and 50% serum, respectively [68]. Recently, Fathi, et al. [69] by designing a label-free SPR nanobiosensor using AuNPs containing CD133 biomarker, pictured a high correlation (R2=0.96) between flow cytometry and SPR nanobiosensor methods in acute myeloid

17

leukaemia cancer detection. Besides, Ermini, et al. [70] by applying SPR nanobiosensors based on AuNPs modified with thiol layer and streptavidin, and containing carcinoembryonic antigen (CEA), in addition to improving biomarker binding efficiency and reducing nonspecific sensor response, were able to accurately evaluate tumor samples in standard and serum solutions in comparison with conventional methods (Fig. 1B).

4.2.2. SPR nanobiosensors for high-throughput screening SPR nanobiosensors not only analyze ligand-receptor interaction, but can also be used in detecting drugs or any kinds of molecules, pathological or genetic defects, and diagnosis of diseases. In this field, in the diagnosis of sexually transmitted diseases caused by bacterial infections, Soler, et al. [71] by designing lable-free Au nanoholes array-based SPR nanobiosensors modified with protein A/G that integrated with microfluidics were able to detect Chlamydia trachomatis with 300 colony forming units (CFU)/mL and Neisseria gonorrhoeae with 1500 CFU/mL in urine fluids (Fig 1C). Moreover, microRNA (miRNA) assay, nowadays used to detect cancers, syndromes, etc., which can be revealed based on the SPR band difference of AuNPs. In this regard, Hong, et al. [72] improved the recognition of miRNA up to 500 pM for miRNA-200b by applying oligodeoxynucleotide (ODN)-modified AuNPs and competing with miRNA for probe adsorption on Au films. Furthermore, they showed that the use of polyethylene glycol on ODN-modified AuNPs could increase the sensitivity of the biosensor due to the decrease in the ratio of ODN to NPs for surface modification [72]. Recently, Godoy-Reyes, et al. [11] using boronic acid and aldehydeterminated ligands loaded on AuNPs, designed a SPR nanobiosensor for detecting neurotransmitter norepinephrine (NE), which, in addition to reproducibility of fabrication and high-speed speed, and robustness of the nanobiosensor, increased the LOD up to 0.07 µM in aqueous media and 0.09 µM in the urine. NE detection in SPR nanobiosensor carried out

18

based on a variation in wavelength and RI along with color change from red to blue in colorimetric probe. Also, NE can be used as a biomarker for diagnosis of pheochromocytoma and paraganglioma tumors.

5. LSPR nanobiosensors based on plasmonic AuNPs Plasmonic development, especially by noble metals like Au, has led to tremendous progress in the highly sensitive diagnosis of different types of diseases and various biomolecules at molecule levels [73]. In this regard, there are almost three categories of plasmonic nanosensors to be found which include: (a) low sensitive RI nanosensors with multitasking ability [74], (b) moderate sensitive colorimetric nanobiosensors based on the plasmon coupling [75], and (c) the improved sensitive nanobiosensors based on the growth of the NPs [76]. Moreover, when noble metals are typically exposed to light, the LSPR phenomenon can be revealed. This physical characteristic changes with the size of the metal on a nano scale and leads to a local surface plasmon. AuNPs show a high absorption coefficient and dispersion characters at visible to NIR wavelengths regardless of the size, shape, and environment of the dielectric [77]. Also, due to the simple preparation, clear and intense colors, tunable optical properties, sensing low-level, and label-free analytes in physiological media the application of AuNPs based surface plasmon has attracted a great deal of attention. When the AuNPs are irradiated, transferring electrons fluctuate with a resonant modulation, which makes them as a great potential on bio-sensing platforms in immunoassay-based biosensors [78].

5.1. Principals of LSPR biosensors Despite the many ways to develop a powerful LSPR nanobiosensor such as chemical synthesis, electron beam lithography, nanoimprint lithography (NIL), as well as a variety of

19

designed nanobiosensors such as optical based sensing, chip based sensing, and solutionphase based sensing, only several factors including sensitivity, resolution, and figure of merit (FOM), are used for comparing nanobiosensors [79]. Basically, measurements in the LSPR nanobiosensors are based on the RI modification of the surrounding that caused the difference in the LSPR peak wavelength. The LSPR peak is usually measured via spectral extinction on a solid film or based on spectral scattering on single NPs. To understand the relationship between the LSPR peak wavelength and the dielectric performance of the environment, the Drude model can be used following (equation 22): Equation 22: 1 = 1 −

7P2 72 + \2

Where, ωp and γ are the plasma modulation and the bulk metal damping parameter, respectively. In NIR and UV-visible frequencies, the ωp is larger than γ, so the equation 22 converted to equation 23: Equation 23:

1 = 1 −

7P2 72

Then, using the equation 23 and the resonance condition (ε1=-2εm), equation 24 is expressed as following: Equation 24: 7max =

7P

]2m + 1

Here, ωmax is the LSPR peak modulation. Finally, based on conversion of the frequency to wavelength (via: λ=2πc/ω) and the dielectric constant to the RI (via: εm=n2), equation 24 changes to equation 25: 2 +1 Equation 25: max = P ^2(m

Where, λmax and λp are the LSPR peak wavelength and the wavelength related to the bulk metal plasma modulation, respectively. As shown in equation 22 determined which the LSPR peak wavelength dependence on the RI in the optical frequencies is nearly linear. Hence, the RI sensitivity for bulk metal or layer (equation 26) of an AuNPs is described by the ratio of ∆λmax to ∆ns.

20

Equation 26: Sbulk

or layer

=

Δmax Δ(s

The resolution is introduced as the minimum LOD, which, unlike SPP-based sensors, localized SPP has a specific resolution for recognizing the signal. This resolution can be enhanced by changing the magnitude and geometry of the nanostructure (Table 1). An increase in the size of Au nanorings from 100 nm to 210 nm, the maximum extinction wavelength from 798 nm to 952 nm is strongly reduced [80]. On the other hand, the geometric change of Au nanorings by growing the ion milling time causes a change in the extinction spectrum, which is because of the strong interaction between the internal and external surfaces of the ring structure in the NPs [80]. Besides, experiments show that anisotropic NPs display higher reflective index sensitivity than spherical NPs [81]. The RI sensitivity of Au nanorings is about 250 nm/RI unit (RIU), while AuNSPs sensitivity is 60 nm/RIU which is approximately 6-fold lower than Au nanorings [9]. Also, the utilization of the FOM with the definition of the ratio of the RI sensitivity to the resonance wavelengths ∆λ is recommended for determination of sensors performance (equation 27). Equation 27: Figure of merit =

S Δ

Since FOM's calculation for complex plasmonic nanostructures (in various and nonuniform forms) is relatively complex, Becker, et al. [82] proposed alternative equation 28. Based on this equation, all simple and complex LSPR nanobiosensors are comparable 0E 0 Equation 28: Generalized figure of merit = j k E

according to changes in intensity (I) and peak wavelength. U



5.2. Optical fiber-based LSPR nanobiosensors Optical fiber-based LSPR nanobiosensors including evanescent wave absorption, fiber Bragg meshing, long period meshing, and interferometer demonstrate several benefits such as unlabelled real-time recognition, low sample volume, simple design, cheapness, aptness for

21

field applications, remote sensing, and electromagnetic interference resistance [83]. After fabricating the first optical fiber-based LSPR nanobiosensor with AuNPs by Cheng and Chau [84] which was high sensitivity to the local RI variation, many efforts have been done to construct an optical fiber-based LSPR nanobiosensor like LSPR optical probe using AuNPs by Mitsui, et al. [85]. In the following, it was determined that by increasing the dimensions of the AuNRs-based LSPR nanobiosensors from 2.6 to 3.1, 3.7, and 4.3 nm, their index sensitivities increased from 269 to 401, 506, and 766 nm/RIU, respectively, in the RI range of 1.34 to 1.41[86]. It was also found that with increasing the RI sensitivity, the diagnosis of biological substances is achieved more efficiently. At the same time, Sanders, et al. [87] with the design of LSPR optical fiber nanoprobe with an PSA monoclonal antibody layer on Au nano-disk arrays immobilized on fiber, were capable to detect the free prostate PSA in an mouse model with a LOD of 100 fg mL-1 with RI sensitivity at ~226 nm/RIU. Nonetheless, due to the drying of biomolecules in the optical fiber LSPR nanobiosensors, which can increase the measurement error, Kim, et al. [88] by integrating the nanobiosensor in the microfluidic channels, corrected the LOD of the PSA up to 124 fg mL-1 and increased RI sensitivity in nanobiosensor compared to previous methods. Furthermore, it has been shown that optical fiber-based LSPR AuNRs biosensor in addition to overcoming the limitations such as portability, operation simplicity, low selectivity, improved the detection of ochratoxin A in real grape juice samples with the LOD of 12.0 pM in the range of 10 pM to 100 nM [89]. The next challenge in LSPR optical fiber nanobiosensors is the low stability of AuNPs on the fiber layer. Recently, it was determined that with increasing stability of the plasmonic AuNPs on the fiber surface in the LSPR optical fiber nanoprobe through seed-mediated growth, as well as improving the RI sensitivity and resonance intensity, the LSPR nanobiosensor performance increased in the thyroglobulin diagnosis with a LOD of 0.19 pg mL-1 and the detection range between 1 pg to 10 nm per mL (Fig. 2A) [90]. Also, Ko, et al.

22

[91] by using LPSR optical fiber containing AuNPs-clusters, were able to increase 260-fold LOD of Parkinson's biomarkers. This method of detection is then able to compete with current method like ELISA.

5.3. Chip-based LSPR nanobiosensors One of the commonly used LSPR nanobiosensors is the chip-based nanoprobes, which generally consist of immobilization of AuNPs on a flat substrate such as SiO2, and fibers. In this case, AuNPs are generally fabricated by lithography approach and growth on the substrate through suspending the substrate in a NPs solution [92]. After loading AuNPs onto the surface, they can be functionalized with different receptors for various activities [86, 93]. Afterwards, a UV-visible spectrophotometer is applied to measure the absorption spectrum of nanobiosensors. In this regard, Marinakos, et al. [94] via designing a LSPR chip nanobiosensor according to biotin-modified AuNRs with RI sensitivity of 252 nm/RIU, were capable to recognize streptavidin with a LOD of 0.005 µg/mL (94 pM) in PBS and 1 µg/mL (19 nM) in serum with a linear range of 94 pM to 0.19 µM and RI sensitivity of 252 nm/RIU, through changes in the LSPR wavelength and local RI. It was also discovered that the chipbased LSPR nanoprobe based on AuNRs-modified with aptamer increased the LOD of thrombin molecules up to ∼278 pM with a range of 0.25 to 10 µm relative to conventional

methods [92]. In this regard, Huang, et al. [80] developed a LSPR-based nanobiosensor containing Au nanorings on a chip through nanosphere lithography that had a RI sensitivity of 350 nm/RIU and a FOM of 3.1 for DNA probing. Furthermore, measuring the hepatitis B antigen level deposited on AuNRs was developed by changing the LSPR NP from 700 to 750 nm in blood and serum with a concentration of 40 times less (LOD of 0.01IU mL) than that of ELISA kits [95]. Whereas, Aćimović, et al. [96] to increase the reproducibility and repeatability and efficiency of the LSPR chip nanoprobes based on AuNRs modified with

23

markers, integrated the LSPR chip with 8-channel microfluidics, which simultaneously was able to detect biomarkers of human α-feto-protein and PSA, up to 500 pg mL-1 in 50% of serum. Furthermore, Hu, et al. [97] by using AuNPs on a indium tin oxide glass substrate established an LSPR chip nanosensor, in addition to detecting microRNA-21 (was associated with all the cancers) with a LOD up to 3 nM, was able to increase the accuracy of detection compared to conventional methods. Analogously, chip-based LSPR nanobiosensor based on AuNPs modified with oligonucleotide (40 base) were designed, which, in addition to rising the detection speed of Salmonella typhimurium in pork meat up to 30-35 min, increased its LOD up to 104 cfu/mL [98]. Salmonella typhimurium assay was performed based on changes in the RI sensitivity and peak of LSPR wavelength. At the same time, Baquedano, et al. [99] expanded a LSPR plasmonic nanobiosensor based on AuNPs by soft lithography, which has a diagnostic resolution of 1.56×10-5 RIU with a resolution of 1sin an area of 0.75×0.75 mm2. Meanwhile, Kim, et al. [100] in order to increase the detection of hepatitis B virus, developed a LSPR chip nanoprobe based on HBsAg-modified AuNPs that not only increased the LOD from 10 pg to 100 fg per mL, but also improved the speed of diagnosis of the hepatitis B up to 10-15 min without any non-specific binding. Indeed, this nanosystem was able to increase the sensitivity up to 100 times more than the current methods. Moreover, Kumari and Moirangthem [101] by using a chip-based LSPR plasmonic nanobiosensor based on AuNPs immobilized on glass capillary compared to conventional sensors, were able to detect 10 nM of rabbit immunoglobulin G (IgG) and anti-rabbit IgG by increasing the surface binding sensitivity up to 409 pg/mm2. At the same time, based on the quasi three-dimensional (3D) structure of the AuNPs in the form of a chip-based LSPR nanobiosensor, it was possible to detect A549 cancerous cells with a very low concentration of 5×103 cells in mol L-1 in a low sample volume of 2 µl

24

(Fig. 2B) [102]. The quasi-3D chip-based LSPR nanobiosensor designed by Zhu, et al. [102] composed from Au nanosquares on top of SU-8 nanopillars, asymmetric Au nanoholes in the middle, and asymmetric Au nanotubes on the bottom, due to the higher electromagnetic field severity, higher plasmon biosensing region, and longer plasmon decay length compared to two-dimensional plasmonic nanostructures is very suitable for plasmonic LSPR nanobiosensors. Accordingly, recently Peixoto, et al. [103] designed a AuNRs-chip biosensor compared to solution-phase AuNRs biosensor not only able to increase RI from 196 nm RIU−1 to 297 nm RIU−1, and FOM from 2.2 to 3.0 RIU−1, but also improve albumin detection by up to 18%.

5.4. Solution phase-based LSPR nanobiosensors Unlike other methods, in this type of nanobiosensor, AuNPs containing ligands or receptors are suspended inside the liquid and can monitor the corresponding reactions. In LSPR solution phase nanobiosensor, it is necessary to slowly rotate or centrifuge the samples to achieve a potential interaction of functional molecules with NPs [104]. Generally, in this method, solution-based LSPR nanoprobes use LSPR sensors based on RI changes as well as LSPR measurements based on NPs accumulation [105]. In both methods, in addition to changing the LSPR wavelength in the presence of the analyte, the color changes are sometimes visible, which can simplify the examination approaches [73]. In this field, Zhu, et al. [104] and Wang, et al. [106] were able to detect magnesium and potassium ions with a LOD of less than 0.1 mM and 0.1-100 µM, respectively, based on changes in solution color during interaction and maximum wavelength by aptamer-based LSPR sensors (nicking endonuclease and enzyme of E. coli, respectively)-modified AuNSPs (Fig. 2C). Likewise, solution-phase sensors based on AuNPs modified with single-stranded DNA were able to detect Hg2+ with a LOD of 8 nM in fresh and tap water [107].

25

5.5. Comparison among of SPR and LSPR nanobiosensors The function of the SPR and LSPR nanobiosensors is due to the high sensitivity of plasmon couplings to dielectric constant of the media. The SPR nanobiosensors detect variations of the medium RI with a sensitivity of about 1,400 nm/RIU [108]. Nevertheless, long decay and extreme sensitivity increase signal-to-noise costs. Therefore, the best way to reduce the signal-to-noise cost in identifying biomaterials is to reduce the volume of the surface susceptibility [78]. The LSPR nanobiosensors like SPR nanobiosensors are highly sensitive to medium RI. But, LSPR nanobiosensors increase the signal-to-noise ratio significantly, due to the because of processing in the much smaller surface area compared to SPR nanobiosensors. Hence, LSPR nanobiosensors are expanded to single-molecule levels in comparison with the SPR nanobiosensors. Therefore, the target molecule must not be connected to the area outside the probe location. Hence, the main concern of using the LSPR nanobiosensors is their strict tunable nature as a probe (Table 2). On the other hand, by increasing the thickness of the layer in the LSPR nanobiosensors, the sensitivity of the system decreases compared to the SPR nanobiosensors. In this line, Zalyubovskiy, et al. [109] showed that by increasing the thickness of the layer from 10 to 20 nm, the sensitivity of the LSPR nanobiosensors decreased while the SPR nanobiosensor performance was improved.

6. SERS nanobiosensors based on plasmonic AuNPs Although, Raman spectroscopy is considered as a promising approaches in development of nanobiosensors due to excellent chemical properties, easy operation, no water interference, multiplexing detection capability, single-molecule sensitivity, and the need for low sample size in biological assays, it is inherently a weak technique that can be improved by resonance Raman effects or SERS [110]. The integration of these two methods

26

together with chemical enhancement can improve SERS nanobiosensors in biomolecular detection. Since, Raman scattering is a non-photon scattering that occurs via the interaction of light and a molecule, therefore most scattered photons have the same energy as incident photons [111]. Based on this hypothesis and amplifying the Raman signal, the SERS technique could be applied as a molecular fingerprint for passive molecules.

6.1. Principals of SERS nanobiosensors Despite the enhancement of the intrinsic Raman efficiency through plasmonic activities of AuNPs, SERS activities have received more attention due to the poor intrinsic cross-section of the Raman process involving only one photon scattering in 107 photons [112]. The power of Raman and SERS signals can be explained by equations 29 and 30, respectively [113]: Equation 29: PRaman=KNIσRaman Equation 30: PSERS=GSERSPRaman where, K is a constant number for the quantum efficiency in the detector, N is the elucidated molecule number, σRaman the differential Raman cross-section in molecule, and I the laser severity. Also based on equation 31, electromagnetic (Gem) and chemical (Gchem) effects are needed to fortify GSERS. Equation 31: GSERS=GchemGem The effect of electromagnetic changes is more effective than the other factors like chemical modifications. In a point of fact, Gem modification can generate values up to 109-1010 in a hot spot, which strongly depends on the gap size of the adjustable [114]. The calculated Gem is calculated based on the following equation [115]: 2 2 n'32 o<  n'32 o  (  A > A Equation 32: m = > n0 n0

27

where E0 is the electric field of the event light, Eloc indicates the value of the local field at the specific point, νL and νRaman=νL+νStokes are the laser and the Raman scattering modulations for the vibrational state with energy νStokes, respectively. This equation reveals that in local area amplification, the metal substrate performs two roles of enhancing the light signal at the metal surface and amplifying the Raman scattering rate by molecules. Therefore, the effects of chemical modification of the surface on SERS activities are still under investigation, while experimental results suggest that this part can enhance SERS activities by generating Raman signals through the charge transfer between the molecule and the metal. This phenomenon can be described by the ratio between the Raman cross-section of the chemical molecule localized on the metal (σads) and the "free" molecule (σRaman) according to equation 33 [115]: Equation 33: Gchem=σads/σRaman Regardless of the chemical modification and electromagnetic activities, the shape of the NPs, as discussed in the preceding section, is effective on the enhancement of SERS. It appears that the greater number of angles and surface bumps of the NPs, the greater SERS performance. In this regard, the results of Li, et al. [116] exhibited that AuNRs had higher performance and enhanced SERS compared to AuNSPs. Also, they showed that SERS amplification by the colloidal state was more than the solitary state of the AuNPs [116]. For instance, in a real saliva sample, even without interfering assay of ascorbic acid and uric acid, it was determined that Au nanostars@ SiO2core shell NPs conjugated with glucose oxidase as a SERS nanobiosensor of provide a stronger signal than individual NPs with a LOD of 16 µM of glucose at a linear range from 25 µM to 25 mM in the aqueous solution [117].

6.1.1. SERS nanobiosensors based on single plasmonic AuNPs Since SERS analysis is a sensitive tool for diagnosis based on competitive exchange and adsorption of ligand, it can be investigated at the level of individual NPs. In this regard,

28

Tebbe, et al. [118] demonstrated the colloidal stability and safety of surfactant-free albuminfunctionalized AuNRs in biological systems (Fig. 3A). However, some concerns regarding the high deposition of the SERS reporter at one site, or the separation of molecules from the surface of the uncoated AuNPs, which caused a profound reduction in the signal, led to the use of a protective agents like SiO2 layer. On the other hand, the protective layer can result in greater NPs solubility and usability in biomass. For example, Tian, et al. [119] using SERSbased nanobiosensor containing individual Au-nanostars@mercaptobenzoic@nanoshell structure modified with cholesterol (B-Chol)-labeled DNA anchor, were able to detect HepG cancer cells higher than conventional method according to the exosomes detection with a LOD of 27 particles per µL and a linear range of 4-40×107 particles per µL. Therefore, this capability of measuring SERS in AuNPs with and without coating has provided much attention for biomedical applications. Recently, based on a novel plasmonic multi layered core-shell-satellite nanostructure (Au@Ag@SiO2–AuNP) modified with biomarker of αfetoprotein, Yang, et al. [120] designed an amplified SERS nanobiosensor capable of detecting cancer biomarker much higher than the conventional methods with a very low LOD of 0.3 fg mL-1 and a linear response from 1 fg mL-1 to 1 ng mL-1.

6.1.2. SERS nanobiosensors based on plasmonic assemblies of AuNPs Although the plasmonic assemblies of AuNPs is complex and diverse, increasing the number of AuNPs, especially in the organized type, in addition to increasing SERS performance, enhances the ability to detect analytes based on plasmonic properties of AuNP [121, 122]. For example, Shorie, et al. [123] with the arrangement of nanosheets of tungsten disulfide and AuNPs along with the aptamer of cardiac myoglobin could develop an enhanced SERS nanobiosensor that was able to detect cardiac dysfunction with accuracy of 10 f/mL to 0.1 µg/mL. Since many assemblies of AuNPs reduce SERS performance due to

29

inappropriate orientations, Lertcumfu, et al. [124] by employing DNA strands in performing assemblies of AuNPs, in addition to increasing speed and accuracy in alignment, reboust SERS signal in microRNA detection with the LOD of 0.12×10−12 M.

6.2. Application of SERS nanobiosensors based on plasmonic AuNPs The development of portable SERS-based nanobiosensors can provide food or environmental safety assays; diagnose a variety of diseases based on biomarkers, and bioimaging devices. For instance, Kong and colleagues in two experiments, showed that the Au and Ag substrate functionalized with a boric acid to capture glucose with labeling metal carbonyl or alkyl group were able to detect glucose in urine without interfering with SERS peak at 2111 cm-1 and 1996 cm-1, respectively [125, 126]. In the following, based on the properties of the AuNPs as peroxidase-mimicking nanozyme along with the transfer of loaded glucose and lactate oxidase [127], Hu, et al. [128] designed an enhanced SERS nanobiosensors to monitor lactate and glucose levels in stroke and brain injury. Indeed, AuNPs@MIL-101@GOx and AuNPs@MIL-101@LOx nanobiosensors in rat model not only was able to determine the glucose and lactate levels in living brain tissue, but also evaluated the therapeutic effect of astaxanthin based on Au nanozyme activities. Since understanding the concentrations of neurotransmitters in different sections of the brain helps in the analysis and care of neurodegenerative diseases, El Alami, et al. [129] by employing AuNPs-based SERS nanobiosensor, were able to monitor the activity of acetylcholinesterase after inhibition with two pesticides of carbaryl and paraoxon, which result in memory loss and impaired neuromuscular function. It was also found that using a SERS-enhanced nanobiosensor by AuNR dimer covered with an Ag shell and Au core-Ag shell NP-Au nanorod heterodimers, improved the detection of dopamine which is associated to Alzheimer disorder, with a LOD of 0.006 pM with a wide linear range of 0.01-10 pM

30

[130] and 0.02-0.04 fM with a linear range was 0.1-10 fM [131], respectively, on PC12 cells. In addition, with application of AgNPs and AuNPs-based SERS nanobiosensors, research was conducted on neurotransmitters such as melatonin, serotonin, dopamine, norepinephrine, GABA, and epinephrine illustrated that the potential detection of the neurotransmitters level from the catecholamine group is related to AuNPs-based SERS nanobiosensor [132, 133]. Whereas, for amino acid chain-based neurotransmitters the maximum recognition was achieved by using AgNP nanobiosensors. Recently, Zhang, et al. [134] by designing the different Raman dye-coded polyA aptamer-AuNPs in SERS-enhanced nanobiosensor, were able to detect Alzheimer disease based on the binding of aptamer to Aβ(1–42) oligomers and the Tau protein present in artificial cerebrospinal fluid samples with high accuracy and high speed (less than 15 min) compared to conventional methods. SERS-enhanced nanobiosensors are an attractive way to track cancer cells because of their high sensitivity, limited volume sample processing, and rapid detection. Thus, Eom, et al. [135] by designing immuno-SERS nanobiosensors based on AuNPs containing aptamer, were able to detect a breast cancer according to aptamer binding to Mucin 1 and altering SERS signal with a LOD of 0.2 cells mol L-1 (Fig. 3B). This procedure is a reliable prognosis for the diagnosis of breast cancer. Similarly, in an mice model, for the internal detection of MCF-7 cell-based breast tumor, Au nano-bipyramids containing 2-naphtalenethiol as a Raman reporter was applied to identify cancer cells below 5 cells in mol L-1 [136]. In this line, Farzin, et al. [137] were capable to recognize breast cancer based on changing SERS signal in the presence of MCF-7 cells with a LOD of 8 ± 2 cells in mol L-1 and a liner range of 10 to 106 cells in mol L-1, with nucleolin loaded on hydroxyapatite nanorods decorated on AuNPs. Analogously, Zhang, et al. [138] were able to detect prostate cancer by change of SERS signal through employing Au nanostars activated with a fluorescent dye, PSA antibody and Alexa 647 as a reporter (Fig. 3C). Also, it was previously determined that assemblies of

31

magnetic NPs (core)-AuNPs satellite containing signal probe and aptamer in the presence of PSA antigens alter the SERS signal to sense PSA in human serum with a LOD of 5.0 pg mL-1 [139]. Besides, Park, et al. [140] by identifying exosomes of two lung cancerous cells including NSCLC and H1299, and normal alveolar cells through using Au nanoshell containing Raman reporter were able to detect cancerous cells based on SERS signal difference between the normal and cancerous exosomes with higher sensitivity than ELISA method.

7. Chiroptical nanobiosensors based on plasmonic AuNPs Chirality is a geometric feature of a structure with mirror asymmetry that was discovered by Arago on the basis of the passage of light from quartz crystals between two optical polarizations [141]. In other words, this parameter can represent fascinating optical effects [142]. Molecules with two or more enantiomeric states show the chirality characteristic measured by the circular dichroism (CD) technique. In principle, chirality can be displayed by molecules having different spatial configurations and inducing different physiological responses [143, 144].

7.1. Chiroptical effects In bianisotropic condition, the optical response is evaluated in a chiral medium, based on equations 34 and 35, which include the subset of magnetic and electrical fields connected together [145]. While for isotropic conditions, the ε, µ and X parameters are scalars in a simplest way.

  p + q0 q p 20  Equation 35: : = 0 n + p 20

Equation 34: @ = −

32

where the ε is permittivity , µ is permeability , χ is chirality tensors , ε0 is the permittivity, µ 0 is permeability of vacuum , E is the electric field , H is the magnetic field , D is the electric displacement is D and B is the magnetic induction. The RI is distinct for right- and leftcircular polarizations, which are explained by equation 36: Equation 36: (± = ]q ± . According to equation 36, it could be confirmed that the difference in the RI between two polarized waves resulting to the linear polarization rotation with an angle: ɸ=(n+-n-)πl/λ, where n+ and n- indicate the RI for left- and right-hand circularly polarized light, l and λ are the depth of the chiral medium and the wavelength in vacuum, respectively. Alternatively, the rotation angle was calculated by ɸ=[arg(T+)-arg(T-)]/2, where T+ and T- are the transfer modulus for two spin modes. Furthermore, the difference in the RI for right- and left-handed polarized indicates that the light provides a thickness differences. On the other hand, equation 36 indicates that if the χ is robust, a negative index can be created for a circular polarized light even if ε and µ are positive [146, 147]. It should be noted that the timing of examining CD processes is very fast due to the speed of light absorption or scattering. The velocity in molecules is associated with their power of rotatory, Rab=µab×mba, where, a and b are molecular modes, µ and m are the electric and magnetic dipole transition instant, respectively. Therefore, for the CD event, the parameters µ and m should be equivalent, which does not happen for asymmetric molecules [148, 149]. In a linear optical patterns, polarization induction is linearly proportional to the electric field of light, which is investigated with P= χ(1)×E, where χ(1) is the linear electric sensibility.

For higher electromagnetic fields, the following harmonics emerge:

P=χ(1).E+χ(2).E.E+ χ(3).E.E.E. In this case, χ(2) and χ(3) are the nonlinear sensibilities related to light scattering in the second and third harmonics, which indicates nonlinear expansion. The

33

next harmonic reply can be explained by a nonlinear polarization in the electric bipolar calculation (equation 37) [150]:

Equation 37: "< 27 = # ∶ n# 7 n 7 2

where χ(2) is the second sensibility tensor, ω is the light modulation, E(ω) is the electric field part of the event light and i, j, k are the Cartesian indexes. On the other hand, nanomaterials are generally effective on the analysis of optical effects through the scattering parameter [151], which makes much more sophisticated estimation [152]. Therefore, the optical response of nanomaterials, which is the easiest way to examine their properties, can be used to describe the optical effects without complexity through the Jones matrix (equation 38 and 39) [153].

n r wA = > n rw  Equation 39: >nw A = > t  n t w

Equation 38: >

rw n A> wA = R rww n t w n A > wA = T t ww n

n > wA n n > wA n

In this equation, the reflection matrix (R), transfer matrix (T), and Ei, Er and Et are the incident, reflected and transmitted electric fields polarized along the x or y direction, respectively.

7.2. Enhancement of chiroptical effects AuNPs, in the presence of other NPs or molecules, have higher chiroptical effects relative to the free form. The reason is due to the enhancement of the chiral field in the nearfield area, which is known as the superchiral field which can be effective in nanobiosensors to identify a molecules [154]. To determine the enhanced chirality C of a pseudo-scalar in the unit time is used based on equation 40 [155, 156]. Equation 40:
, =

1 1 @, . ∇ × @,  0 n, . ∇ × n, + 2 q0

where E is the time-dependent electric and B is magnetic fields. It has been shown that chirality C quantity is closely related to the rate of chiral molecule stimulation. By increasing

34

the chirality C at the site of chiral molecules, the sensitivity for the detection of molecules in biosensors can also be increased [157]. For time harmonic fields, chirality C can simplified to equation 41 [158].

Equation 41:
 = − 70 Im yn ∗ r . @  { 2

Based on equation 8, Govorov, et al. [159] described that the interaction of the AuNPs with the molecules reduces their symmetry and thereby created a CD signal.

7.3. Intrinsic effects of chiroptical in AuNPs Chiroptical effects in AuNPs are derived from high Miller index surface, relaxation of surface atoms due to changes in atomic pattern arising from molecular absorption, and the shape or assembly of AuNPs in a chiral geometry [142, 143, 160, 161]. It should be noted that the chiroptical effects in the molecules are usually small because of the chiral sequence of molecular bonds. The chiroptical properties of AuNPs can be influenced by their type of assembly or morphology. In particular, it is possible to increase optimized chiroptical effects in NPs by collecting AuNPs in origami systems like DNA or fibers [162-164]. This feature is very useful in making a variety of nanobiosensors with a high detection capability.

7.4. Synthesis and application of chiroplasmonic AuNPs 7.4.1 Synthesis Optical chiral AuNPs commonly can be produced by the top-down and bottom-up procedures. Although, top-down manufacturing methods are capable of producing nanostructures with dimensions less than 100 nm, they are usually non-scalable, long-term, and high-expensive. While, the assembly method of a bottom-up, in addition to being the most cost-effective strategy, it could be highly configurable, feasible, and fast. Consequently, the fabrication of chiral plasmonic AuNPs with DNA, cellulose nanocrystals, cholesteric liquid

35

crystals, cysteine, and peptides [165-167], which is bottom-up procedure, could be much more appropriate. The production of chiral plasmonic AuNPs is typically done using chiral thiolated stabilizers like glutathione and penicillamine [168, 169]. The popular technique for DNA assembly is the reformation of supplementary strands of single-stranded-DNA with AuNPs and subsequent hybridization [170]. After creating DNA patterns, the 3D structure of plasmonic AuNPs can be formed. Actually, some studies have shown that high chiroptical effects will occur at 542 nm in the case of plasmonic AuNRs [171]. Further procedures such as the application of a linkers in combining the two single-stranded-DNA strands on the AuNPs surface, as well as creation of double-stranded-DNA before connecting to AuNPs surface are documented to be feasible [172, 173]. Since the chain length, type of linker, and sequencing are effective in assembling the chiral plasmonic AuNPs, then any change in each of these factors will indirectly affect the CD signal [174]. In addition to the type of sequence and linker, the results of Jiang, et al. [175] displayed that changing the amount of glutathione and restriction enzymes and changes in environmental pH cause a change in CD intensity. Accordingly, it was determined that the decrease in the amount of glutathione and the restriction enzymatic activity triggered irreversible variation in the plasmonic CD signal, while the environmental pH and photoradiation parameters caused reversible changes in the plasmonic CD signal.

7.4.2. Application Chiral structures have been extended to produce nanobiosensors specifically for the detection of antibiotics, cancers, DNA, and so on. Because the assembly of plasmonic AuNPs, which include plasmonic NPs and chiral molds, are more effective in absorbing and scattering light relative to molecules. Therefore, the design of nanobiosensors based on chiral plasmonic AuNPs was more considered in comparison with other cases. For example, Su, et

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al. [176] by applying a chiral N-acetyl-l-cysteine-capped AuNPs (with diameter of 6-8 nm) were able to measure the L-tyrosine acid through a colorimetric sensors (Fig. 4A). The minimum concentration of L-tyrosine needed to change the color and produce a signal in the colorimetric sensor based on chiral AuNPs was 25×10−6 M. Moreover, Liu, et al. [177] developed nanobiosensors according to DNA-directed chiral AuNP dimers, which, in addition to measuring the DNA MTase (endonuclease HpaII) with high selectivity and sensitivity, was able to control the sample in complex states in the presence of human serum. The recognition mechanism was according to the separation of AuNPs from the chiral complex due to the attachment of the complex to HpaII, and the reduction of CD signal intensity. At the same time, Tang, et al. [178] using chiral plasmonic AuNRs dimers, designed a nanobiosensor to detect of the PSA, which by enhancing the CD signal, significantly increased the LOD up to 0.076 aM with a linear range of 0.1 to 50 aM. Also, a cancerous probe based on the assembly of Au-quantum dot nanocomposites was designed in the form of DNA scaffolds for catalytic imaging of cancer-related microRNAs, This system was able to capture cancer cells 3-fold more than commonly used methods in living cells, due to the increased CD signal intensity (Fig. 4B) [179]. Besides, Zhao, et al. [180] with the use of Au-Ag NPs connected to the aptamers in a chiral structure, were able to amplify CD signals when the human epidermal growth factor receptor 2 antigen was present in cancerous cells. Based on this procedure, the chiral AuNP dimers were developed to chiroplasmonic sensor for detecting and measuring α-fetoprotein (αFP) antigens from liver tumors with a LOD of 11 pg mL-1 and with a linear range from 0.02 to 5 ng mL-1 [181]. The detection mechanism was based on the attachment of the aptamer to the αFP and the linear reduction of the CD signal intensity (Fig. 4C). Likewise, based on the assembly of AuNPs and graphene oxide on the DNA scaffold, Ma, et al. [182] designed chiral complex probe that detects epithelial cell‐adhesion molecule (EpCAM) with a LOD of 3.63 pg mL-1

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and detection range between 8.47 to 74.78 pg mL-1. The detection mechanism was based on the release of AuNPs and the reduction of the CD intensity when EpCAM was interacted with the chiral complex. In the following, the chiral nanobiosensors based on DNA scaffolds and Au shell-core could provide a higher detection of mycotoxin, ochratoxin A with a LOD of 0.037 pg mL-1, with a detection range of 0.1–5 pg mL-1 compared to common sensors, due to amplification of CD signal intensity [183]. In addition to DNA scaffolds, Kumar, et al. [184] by applying β-amyloid peptide scaffold and AuNRs, developed a chiral nanobiosensors for the diagnosis of Alzheimer dementia that were able to diagnosis diseases through α-synuclein detection down to nM concentration (Fig. 4D). On the other hands, chiral AuNPs dimers have excellent intracellular stability and biocompatibility, thus they are used to detect processes or intracellular molecules. In this line, Fu, et al. [185] using a hetrodimers of chiral plasmonic AuNPs based on DNA scaffolds, not only monitored adenosine triphosphate (ATP) in living cells, but also measured it in intracellular medium with LOD of 0.2×10−3 mM and with a detection range of 1.5×10−3 to 4.2×10−3 mM. However, it was found that dimers of chiral plasmonic AuNPs in the transition to cytosol of living cells alter the flux of the plasma membrane from negative to positive, which can cause large electrostatic changes in living cells [186]. Therefore, these dimers can be effective in photodynamic therapy (PTT), in addition to imaging activities.

8. Conclusion and outlook Since AuNPs show some novel characteristics, including intrinsic electrical properties, plasmonic hybrid performance, intense light emissions, multi-analyte assay, easy production, high stability, biocompatibility, and very low toxicity, researchers have aimed to use this materials in plasmonic optical nanobiosensors to increase sensitivity, selectivity and

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synchronization of a variety of biosensing, imaging and even therapeutic activities in realtime monitoring. On the other hand, SPR, LSPR, SERS and chiroptical nanobiosensors show some limitations such as signal reproducibility, standardization, high sensitivity and selectivity, and the need for confirmation with conventional methods that can be controlled and enhanced by applying plasmonic NPs, especially AuNPs. For this reason, SPR, LSPR, SERS and chiroptical nanobiosensors containing plasmonic AuNPs have been included in countless diagnostic applications. Despite the structural differences, and the different advantages and disadvantages among the different nanobiosensors (Table 2), almost one common factor, namely continuous improvement of high-sensitivity detection, has attracted a great deal of interest in nanobiosensor filed. However, efforts to find the best applications of optical plasmonic nanobiosensors coupled with the most suitable AuNPs in terms of shape, size, individual or integration with other nanomaterials remain active in diagnostic activities. In this regard, very important challenges are observable, including: (1) Improving diagnostic certainty of analysts: diagnostic activities continue to face major challenges due to lack of proper assembly or arrangement of AuNPs. Although some experiments have shown higher sensitivity with the use of AuNPs in optical nanobiosensors, the sophisticated methods of manufacturing, the high cost of production, the correct understanding and availability of the developed tools, and the need for complex examinations before their practical applications prevent their wide-spread utilization in clinical settings. (2) Optical nanobiosensors miniaturization and development: for the use of optical nanobiosensors in clinical applications such as screening and disease detection, it is necessary to speed detection time and provide several experiments in one sample in addition to easy nanobiosensor portability and reduced sample size. For this purpose, in addition to changing the nature of the devices from microarrays to nanoarrays, NPs with unique properties such as

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plasmonic Au and Ag NPs should be integrated as independent units. However, due to the lack of comprehensive approaches in nanostructures fabrication, instrumentation problems, and expensive along with variable responses, the production of plasmonic AuNPs based optical nanobiosensors in the operational phase is hampered. (3) Simplifying the detection method: one of the major challenges in nanobiosensors, especially the optical type, is the complex process of preparing and detecting analytes. Despite the efforts to develop simple transducers, the use of optical nanobiosensors in small laboratories and open environments continues to be restricted. In this regard, the use of colorimetric methods has somewhat mitigated these problems, but the low sensitivity is one of their limitations. Given the early achievements and advancement of multiplexed assay of analytes by plasmonic AuNPs-based optical nanobiosensors, it can be surely claimed that plasmonic optical nanobiosensors will have a significant impact on the future of diagnostic activities.

Conflicts of interest The authors have none to declare.

Acknowledgment This research was made possible by the grants NPRP10-120-170-211 from Qatar National Research Fund (QNRF) under Qatar Foundation and GCC-2017-005 under the GCC collaborative research Program from Qatar University. The statements made herein are the sole responsibility of the authors.

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Table 1. Characteristics of plasmonic AuNPs sensing Chung, et al. [79]. Wavelength Nano shape Size (nm) Characteristic (nm) Rods 800-1000 Radius 40 Size-dependent LSPR Colloidal 450-600 Diameter 30 Size-dependent LSPR Shell 400-800 Thickness 4.5 Size-dependent LSPR Disk 500-1000 Pitch of nanodisk: Anisotropic 162 and 340 property Ring 500-1700 Outer diameter: 120 Plasmon hybridization trimmers Wall thickness: 33 Ring height: 24

Sensitivity (nm/RIU) 650

RI range 1.3-1.7

71

1.3-1.5

408

1.3-1.5

167 and 327

1.3-1.4

345

1-1.5

Table 2. Advantages and disadvantages of using SPR, LSPR, and SERS biosensors to monitor biomolecules. Type of nanobiosensors SPR

LSPR

Based-SERS

Advantages

Disadvantages

LOD

Label-free environment, real-time, continuous measurement, quick testing, small sample, highly sensitive, specific to the binding event, and measurement of active concentrations in absence of a standard sample Ease of operation, possibility of high-throughput sensing, label-free environment, real-time, small sample, and quick test. High specificity, multiplexing capabilities, available for fingerprinting, increased detection sensitivity, rapid signal acquisition times, conduction under ambient conditions, broad wavenumber range, narrow band spectra

Immobilisation effects, nonspecific binding to surfaces, mass transport limitations, misinterpretation of data, expensive

µM to pM

Not able to distinguish different binding events regarding multiple analytes,

>pM

poor signal reproducibility, difficulty in the precise and cost-effective fabrication of nanostructures, requirement of interdisciplinary research for development of highly sensitive and reliable system

>aM

1

Figure 1. SPR plasmonic AuNPs biosensors. (A): Cancer prognostic miRNA biomarkers; (a) Schematic illustration of the SP-LS scheme for the detection of miRNA. Typical SPR angular spectra for refractometric SPR and SP-LS measurement for the (b) target miRNA-122 (100 nM). MiRNA-122 measurements and resulting calibration curves using 55 nm AuNP tags for (c) refractometric SPR and (d) SP-LS. (B): Detection of carcinoemberyonic antigen; (a) Schematic of the sandwich-assays using functionalized NPs for the detection of CEA in the three different conditions, (b) SEM image of citrate covered AuNPs deposited on a silicon substrate, (c) Specific SPR sensor responses for Antibody2(Ab2)-AuNPs measured for three ligand doses per AuNP (LDPN). Specific SPR sensor responses to Ab2-AuNPs (d) and relative nonspecific SPR sensor response (RNS) to Ab2-AuNPs (e) as a function of LDPN at buffer PBS. (C): Detection of chlamydia trachomatis and neisseria gonorrhoeae in urine; (a) Schematics of the nano-plasmonic biosensor working principle. Evaluation of the sensitivity and selectivity for the detection and quantification of both bacteria in buffer. (b) Standard calibration for specific detection of Chlamydia trachomatis (CT) (blue). Signals are obtained by flowing CT samples at different concentrations (101– 107 CFU/mL) over a sensor array functionalized with anti-CT antibody. Green triangles represent nonspecific binding of Neisseria gonorrhoeae (NG) on the anti-CT antibody array. (c) Standard calibration for specific detection of NG (green). Signals are obtained by flowing NG samples at different concentrations (101–107 CFU/mL) over a sensor array functionalized with anti-NG antibody. Blue triangles represent nonspecific binding of CT on the anti-NG antibody array. Each data point represents the mean and standard deviation of three replicates. Data is fitted to a linear regression model. Multiplexed analysis of different bacteria in urine. Sensorgrams show the signals corresponding to the three arrays functionalized with anti-CT antibody (blue), anti-NG antibody (green) and the control antibody (red). Horizontal black line serves as reference to identify the urine background signal. (d) Background signal from negative a healthy urine sample. (e) Detection of both CT and NG spiked in the same sample (107 CFU/mL each) (blue and green line).

2

Figure 2. LSPR plasmonic AuNPs biosensors. (A): Detection of thyroglobulin by LSPR biosensors; Schematic diagram of the Au capping process on a surface of an optical fiber. (a) Firstly, AuNPs are immobilized on the optical fiber. Secondly, citrate ions are attached on AuNPs to reduce Au+ ions. Finally, AuNPs are physically absorbed to optical fiber surface owing to the growth of AuNPs by citrate reduction. (b) The FE-SEM image shows that there is no aggregation of the nanoparticles following the Au capping process of 180 min. (c) The test samples with levels unknown to the tester were measured three times at each concentration. (d) The concentrations of thyrogolobolin are measured in human serum. The serum samples are diluted to various levels and detected three times at each concentration. The CVs at each concentration

3

are shown in the inset. (B): Label-Free detection of live cancer cells; (a) 3D multilayered plasmonic nanostructures with Au on top (820 nm), middle (997 nm), and bottom (997 nm). (b) Measured extinction spectra for 3D multilayered plasmonic nanostructures with 31%. (c) Normalized extinction spectra of 3D multilayered plasmonic nanostructures with 56% offset in DMEM medium and with live lung cancer A549 cells of 2×104 and 5×105 cell/ml. (d) Normalized extinction spectra of 3D multilayered plasmonic nanostructures with 56% offset and with probe and complementary target DNA of 10-10 and 10-7 M. (C): Colorimetric detection of magnesium; (a) Rational design of AuNPs-based colorimetric detection of magnesium ions and color response of a 14-nm nanoparticle detection system (∼4 nM particles; 0.3 µM DNA duplex) in the presence (5 µM) or absence of Mg2+. (b) The corresponding TEM images taken for the samples with and without Mg2+. (c) The corresponding UV–vis spectra of the particle solutions with or without Mg2+. (d) Colorimetric response of the detection system (∼4 nM particles; 0.3 µM DNA duplex) in the presence of a selection of metal ions (10 µ M each). (e) Colorimetric response of the detection system (∼4 nM particles; 0.3 µM DNA duplex) in the presence of various PPi contents (0–30 µM) and the corresponding UV–vis spectra of the particle solutions in the presence of different PPi concentrations.

4

Figure 3. SERS plasmonic AuNPs biosensors. (A): Colloidally stable and surfactant-free proteincoated AuNRs; (a) Schematic of AuNR@BSA. (b) TEM images of the AuNR@BSA from. (c) UV/vis/NIR spectra of AuNR@BSA samples before (dashed line) and after freeze-drying (full line). (d) SERS of AuNPs (AuNS: spheres; AuNR: rods) with CTAB (black, top) and BSA (red,bottom) coating dispersed in water and compared with conventional Raman spectra of crystalline CTAB and dry BSA: (1) Counter ion signals; (2) ammonium signals; (3) skeletal chain vibrations (top) and amide bands (bottom); (4) methyl/methylene "fingerprint". The spectra are offset and scaled for clarity and show raw data without background correction. (B): Breast cancer tissues diagnosis by Au nanowire (NW) SERS biosensors; (a) Schematic illustration of nanogap-rich AuNW SERS biosensor fabrication process. Vertical AuNWs are synthesized on a sapphire substrate by using a vapor transport method. Nanogap-rich Au NW is prepared by Au sputtering on AuNW. As shown in SEM image of nanogap-rich AuNW, AuNPs are uniformly deposited over the whole NW. Telomerase activity detection procedure using nanogap-rich AuNW SERS sensor. Thiolated TS primer is attached onto

5

nanogap-rich Au NW SERS sensor. Telomerase is extracted from mouse tumor tissues and incubated with TS primer-modified NWs. TS primer is elongated by telomerase and then folded into G-quadruplex structure. MB is intercalated into the G-quadruplex structure and strong SERS signals of MB are obtained from nanogap-rich AuNW SERS sensor. (b) Intensity of MB 1620 cm−1 band plotted as a function of cell concentration. The arrowtagged data is for 0.2 cells mL−1. Inset provides 1620 cm−1 band intensities of MB at cell concentrations of 0, 0.2, and 1 cells mL−1. SERS signal of 0.2 cells mL−1 is clearly distinguishable from the signal of 0 cells mL−1. Data represent the average plus standard deviation from 7 measurements. (c) NIH3T6.7 (xenograft breast cancer mouse, n = 5) models. Breast tumor tissue samples show strong SERS signals while other organ tissue samples show very weak signals. (C): Detction of PSA by SERS Au nanostar biosensor; (a) SERS probes prepared by coating Au nanostars with a dual SAM of 4-NTB-MEG-OH and 4-NTB-TEGCOOH, and then covalently linked with antibodies (Au starantibody); PEGylated SERS probes prepared by coating Au nanostars with SH-PEGCOOH and supplemented with 4-NTB, and then covalently linked with antibodies (Au star-PEG-antibody). (b) In iSERS microscopy either primary antibodies are conjugated with SERS NPs to perform direct staining (1), or secondary antibodies are conjugated with SERS NPs to perform indirect staining (2). (c) Direct iSERS staining of PSA in HIER-treated prostate biopsies using SERS probes and PEGylated SERS probes. Au star-anti-PSA (1) with the negative control (2). Austar-PEG-anti-PSA (3) with the negative control (4). (d) Indirect iSERS staining of PSA in HIER-treated prostate biopsies using SERS probes and PEGylated SERS probes. Au starA647G@M (1) with the negative control (2). Au star-PEG-A647G@M (3) with the negative control (4).

6

Figure 4. chiroptical AuNPs biosensors. (A): Colorimetric detection of chiral tyrosine based on AuNPs; (a) The possible interaction mode between L-Tyr and NALC–Au NPs. (b) TEM images of NALC– AuNPs. (c) Illustration of separation processes after addition of D- or L-Tyr to NALC–AuNPs followed by centrifugation. (d) All these showed an obvious discrimination between DTyr and L-Tyr. It is operated as follows: 0.5 mL of 10–3 M D- or L-Tyr aqueous solution were respectively added to 1.5 mL of NALC–AuNP colloids and mixed before measuring. (e) NALC–AuNPs response to D- and L-Tyr in the UV-vis absorption spectra, in which the black line is shown as the control, the inset shows corresponding color changes, intuitively indicating the obvious discrimination, and the value of A630/A522 was compared from the histogram. (f) The color, UV-vis absorption spectra of NALC–Au NPs mixed with D- or L-Tyr with increasing concentrations. (B): Imaging of microRNA in living cells; (a) Agarose gel electrophoresis characterization of GNP-QDs

7

disassembly under different C’/L molar ratios in the presence (left) and absence (right) of fuel DNA. TEM images of assembled GNPQDs satellite monomer and dimer, and disassembled reaction products isolated from agarose gel. (b) Live-cell imaging of miRNA-21 in HeLa, MCF-7, MDA-MB-231, and HEK-293 cells. Fluorescence microscopy images of HeLa, MCF-7, MDA-MB-231, and HEK-293 cells treated with GNP-QDs nanoassembly/fuel DNA (left panel) and GNP-QDs nanoassembly only (right panel). (c) Quantitative analysis of miRNA-21 in total RNA extracted from HeLa, MCF-7, MDA-MB-231, and HEK-293 cells. PL intensity (630 nm) of GNP-QDs nanoassembly incubated with total RNA extracted from HeLa, MCF-7, MDA-MB-231, and HEK-293 cells in the presence or absence of fuel DNA. (d) Copy numbers of miRNA-21 per pg total RNA from HeLa, MCF-7, MDA-MB-231, and HEK-293 cells determined by catalytic detection. (C): Detection of alphafetoprotein by chiroplasmonic assemblies; (a) Schematic of fabrication process for detecting of AFP. (b) Statistical analysis of the NPs assemblies, counting the number of monomers, dimers, trimers, and others at different AFP concentrations. (c) Selectivity of the sensing system in the presence of AFP, thrombin, telomerase, MTase, PSA, HSA, IgA. The concentration of AFP was 0.5 ng mL-1, and the concentration of other biomarkers was all 10 ng mL-1. (d) Representative TEM images of AuNPs dimers. (D): Detection of amyloid fibrils in Parkinson’s disease; (a) TEM images of α-synuclein fibrils and TEM images of AuNRs in the presence of αsynuclein fibrils. (b) Extinction and (c) CD spectral changes of Au NRs monitored over a time period of 80 min after the addition of α-synuclein fibrils (80 nM). Each spectrum was collected after a time interval of 20 min. Insets show the (absence of) spectral changes in the presence of α-synuclein monomers (1 µM). (d) Extinction and (e) CD spectra of Au NRs monitored 30 min after the addition of 30 µL of purified brain homogenates from healthy (black traces) and PD-affected (red traces) patients (PD1). (f) Extinction and (g) CD spectra of Au NRs monitored 30 min after the addition of 20 µL of native PrP (black traces) and prion fibrils (blue traces).

8

Highlight This review provides an overview of AuNPs manufacturing methods and their impact on plasmonic activities as well as strategies for enhancing plasmonic properties. We describe recent advances and applications of AuNPs-based plasmonic nanobiosensors in vitro and in vivo modes for diagnostic and imaging activities. In this article, we discuss the trends and challenges of SPR, LSPR, SERS and chiroptical plasmonic nanobiosensors with their equations.

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: