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Review

Metallic Nanoparticles for Surface-Enhanced Raman Scattering Based Biosensing Applications

by
Jiro Karlo
1,
Syed S. Razi
2,
Mahamkali Sri Phaneeswar
1,
Arunsree Vijay
1 and
Surya Pratap Singh
1,*
1
Department of Biosciences and Bioengineering, Indian Institute of Technology Dharwad, Dharwad 580011, India
2
Department of Chemistry, Gaya College, Gaya 823001, India
*
Author to whom correspondence should be addressed.
Photochem 2024, 4(4), 417-433; https://doi.org/10.3390/photochem4040026
Submission received: 8 August 2024 / Revised: 8 September 2024 / Accepted: 13 September 2024 / Published: 26 September 2024
Browse Figures
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Abstract

:
Surface-enhanced Raman scattering (SERS) is a powerful tool for biosensing with high sensitivity, selectivity, and capability of multiplex monitoring for both in vivo and in vitro studies. This has been applied for the identification and detection of different biological metabolites such as lipids, nucleic acids, and proteins. The present review article explores the vast applications of metallic nanoparticles for SERS-based biosensing. We have summarized and discussed the fundamental principles, theories, developments, challenges, and perspectives in the field of SERS-based biosensing using different metal nanoparticle substrates namely gold, silver, copper, and bimetallic nanoparticles.

1. Introduction

The rapid detection and identification of the biomolecule of interest in complex biological matrices comes with greater challenges such as sensitivity and reproducibility as biomolecules are complex and dynamic. One of the feasible label-free and non-destructive approaches for biosensing is aided by the advancement in Raman spectroscopy. Biological samples are natively surrounded by an aqueous environment. However, the Raman biomolecular fingerprint region is not masked by the presence of water. Raman spectroscopy is an analytical technique based on the Raman effect: “the inelastic scattering of photons”. When the light is incident on the sample, one in 106 photons undergoes inelastic scattering which makes it an inherently weak phenomenon. The Raman effect was discovered by Sir Chandrasekhara Venkata Raman in 1928 and published in a paper in Nature titled “A new type of secondary radiation” [1,2]. The conventional workflow of Raman spectroscopy involves the illumination of the sample with a monochromatic light source mostly in the visible to infrared range of the electromagnetic radiation. The inelastically scattered light is filtered and detected using a spectrometer. The output Raman spectra provide characteristic fingerprints of the sample giving out qualitative and quasi-quantitative information [3,4]. Additionally, it comes with versatility with its applicability to the physical state of the sample and the feasibility of multiplexing. However, the spontaneous Raman signals are often weak, which can negatively affect the detection limits. Further, these signals are also susceptible to fluorescence interference and background and system noise. The discovery of surface-enhanced Raman Scattering (SERS) has helped to enhance the sensitivity of Raman-spectroscopy-based biosensing for the detection of a wider range of biomolecules [5]. The SERS technique was first developed by Fleischmann et al. at the University of Southampton, UK. They reported that an adsorbed Pyridine monolayer on a roughened silver electrode showed an amplified Raman signal [2,6,7]. It is a well-known fact that the SERS effect can enhance the Raman signal intensity by 103 to 1012 times [2].
Two primary mechanisms contribute to the working principle of SERS, namely, electromagnetic enhancement (EME—108 to 1012 times) and chemical enhancement (CE—103 to 105 times) [2,8,9]. The SERS enhancement mechanism was explained and demonstrated by Van Duyne, Moskovits, Creighton, and their co-workers [7,10,11,12,13]. EME often occurs due to the excitation of localized surface plasmon resonance (LSPR), which involves the interaction of a strong electromagnetic field generated on the surface of the plasmonic nanostructure within the proximity of sample molecules. This LSPR excitation occurs at the resonating frequency of the incident light, making the EME enhancement mechanism light-wavelength-dependent [14]. Surface plasmons are the volume of oscillating conduction band electrons of metallic nanostructures [15]. When the frequency of incident light resonates with the plasmon frequency of a nanostructure, it leads to the oscillation of the surface plasmons, which induces a localized dipole in the nanostructure as shown in Figure 1. This induced dipole generates an enhanced electromagnetic field, which leads to another induced dipole on sample molecules present in its closed proximity, which in turn, results in the generation of a higher number of photons [2,7]. This whole phenomenon leads to the enhancement of Raman signal intensities, which is dependent on mainly two factors, the strength of the incident electric field and the polarizability of metallic nanostructures [2]. Another SERS enhancement mechanism is CE, which involves the transfer of electrons between the sample molecule and metallic nanostructures that are in close contact or a few angstroms apart. As it is a physio-chemical interaction, the effect is short-range and contributes much less enhancement compared to EME [7]. When the incident light falls on the nanostructure, an excited valence band electron jumps to the conduction band, leaving an empty hole in the valence band of the nanostructure. Due to resonant tunneling, this excited electron present in the conduction band of the nanostructure rapidly transfers itself to a similar energy level above the lowest unoccupied molecular orbital (LUMO) of the sample molecule. However, the electron will transfer back to its original position to fill the empty hole in the valence band in the nanostructure. This process will transfer energy exciting the sample molecules to a vibrational level, which results in the emergence of a Raman photon [7]. Due to this resonance charge transfer and radiated Raman photon, amplification of Raman scattered signal intensities and a noticeable shift in the spectra are observed. This shift occurs due to chemisorption on the geometrical and/or electronic structure of the adsorbed sample molecules [2,16,17]. The schematic diagram presented in Figure 1 represents a pictorial understanding of SERS enhancement mechanisms.

2. SERS-Based Biosensing

SERS-based biosensing is a rapid detection and identification technique that involves the interaction of biomolecules with minimally invasive biocompatible SERS substrates resulting in a multi-fold enhanced sensitivity of the Raman signal and an increased multiplex biomolecular limit of detection [7,14]. Most biological systems are inherently aqueous systems, but due to the very small Raman scattering cross-section of water, Raman signals are minimally perturbed by the background signal from water [14,15,16,17,18,19]. The most widely used SERS substrates for biosensing are metal nanostructures of gold (Au) and silver (Ag), which are noble metals. Another commonly used SERS substrate is copper (Cu), which is comparably reactive but higher in abundance and less expensive [7,14]. Au is chemically more stable and biocompatible, therefore, it is preferred for intracellular/in vivo studies, whereas Ag is less preferred as it is toxic to living organisms [7,20,21,22,23]. The concept of nanotechnology was first introduced by Norio Taniguchi in 1974 [24]. Metal nanostructures/nanoparticles (MNs) are metallic nanoscale particles which are of different sizes and shapes such as nanowires, nanorods, nanoprism, nanostars, nanoflowers, nanospheres, and others [7,10,14,25]. The shape and size of MNs play an important role in developing interaction between adsorbed sample molecules and the plasmonic surface of the nanostructure. Hence, fabricating and designing substrates of appropriate shape and size is crucial for SERS-based biosensing performance. When MN size is greater than 100 nm, multipole excitation occurs instead of an induced dipole, which results in redistribution of total charge within the substrate, leading to non-radiative mode charge transfer decreasing the SERS enhancement. Similarly, shape also plays an important role in the surface volume ratio for the substrate–sample interaction [2,7]. Another important aspect of SERS-based biosensing is the synthesis methods of the nanostructures. For the synthesis of gold nanoparticles (AUNPs), broadly performed methodologies are seed growth, one-step synthesis, and electron beam etching [26,27,28,29]. Like AuNPs, Silver nanoparticles (AgNPs) can be of different shapes and forms such as nanocubes [30,31], nanowires [32], flowered-shaped nanoparticles, and others [33,34]. The efficacy of SERS-based biosensors can be determined by assessing their sensitivity, specificity, and reproducibility. This approach has been used in a wide range of biosensing applications such as pesticide detection [35,36,37,38,39], the identification, characterization, and detection of bacteria and other pathogens [40,41,42,43,44], the detection of other biomolecules [45,46,47,48], and disease diagnosis [49,50,51,52,53]. In this review, we have discussed SERS substrates for biosensing applications where a SERS substrate refers to the metallic structure, which can be metallic nanoparticles in solution (such as water) also known as metallic colloids (colloidal solutions) and planar metallic structure such as metallic nanoparticles arranged in an array on a planar substrate [54]. In the laboratory, SERS is mostly carried out using metallic colloids as these are easy to produce; however, at the same time, a stabilizing agent is required to avoid aggregation. The simplest way to make a planar SERS substrate is by drying the metallic colloidal solution on a suitable substrate, however, this may result in large spatial inhomogeneities [54]. Potential biosensing applications of different metallic nanoparticles are shown in Table 1.

3. Gold-Based Nanomaterials for SERS and Their Applications in Biosensing

Plasmonic nanoparticles have the potential to enhance the Raman signal intensities of the Raman active mode of molecular bonds. Noble metal nanoparticles including Au, Ag, and Cu are typically used as SERS substrates [76,77,78,79,80]. The universality of SERS measurements is hindered by the expensive preparation and disposal problems of these substrates. Anisotropic gold, silver, and copper nanoparticles (NPs) with sharp corners and edges are beneficial for developing biosensors based on MEF and SERS due to the amplified plasmonic effect with incident light frequency in the visible to near-infrared regions [81]. Depending on reaction conditions, it is possible to produce gold nanoparticles (AuNPs) of various sizes and shapes. Based on the shape and size of the AuNPs, they exhibit a unique (LSPR) peak in the visible to NIR range (>500 nm). The redshift of the LSPR peak increments with the aspect ratio, i.e., the length-to-diameter ratio, of the AuNPs. Surface functionalization of metal nanostructures is essential for developing nanoparticle-based biosensors, also known as nano biosensors, as it enables target-specific detection. To prepare the bio-metal detecting nanoprobes, various biofunctionalization and assembling techniques are performed. Indeed, varied sizes, shapes, compositions, aggregations, and coatings can be used to create SERS-active nanostructures, opening the door to response customization for detection needs. The SERS substrate synthesized and fabricated for an incident light source in the near-infrared region minimizes the photodamage to biological samples and prevents auto-fluorescence, which can mask the SERS signal. When we compare AuNPs to other nanomaterial counterparts such as metal-oxide- or carbon-based nanomaterials, AuNPs are widely used for biosensing applications due to their biocompatibility, nontoxic nature, optical properties, electronic properties, and tunability. According to the literature, nanoparticles between 10 and 100 nm in size are more suited for SERS investigations as the size and shape of the nanoparticles play important roles, such as in the occurrence of a multipole, which is a non-radiative mode, rather than a dipole [82,83]. Another important factor to consider for enhancing SERS performance in suspensions of metal nanoparticles is the shape of the nanoparticle. Shapes like nanostars, nanorods, nanocubes, nanoplates, nanostars nano prisms, and others are used for biosensing [84,85].
AuNPs offer higher chemical stability and excellent biocompatibility and are well-suited for excitation in the visible and near-infrared regions [20,21]. Qian et al. reported that active targeting achieved more nanoparticle, specifically gold nanoparticle, accumulation in human tumor xenografts [86]. To confirm the nanoparticle accumulation in the tumor, gold nanoparticles functionalized with Raman labels were employed for SERS imaging in this investigation. Gold ion salts were used to synthesize the nanoparticles, which are functionalized with ScFv B10, which is an antibody fragment known to have specificity for human EGFR; the synthesis was carried out in such a way as to achieve the size that was best for SERS. The cells, namely, human non-small cell lung carcinoma NCIH520, which are EGFR-negative cancer cells, and Tu686, which are EGFR-positive cancer cells, were first incubated with the nanoparticles and the SERS analysis confirmed the uptake of nanoparticles by the EGFR-positive cells. However, there was no discernible SERS signal in the EGFR-negative cells. The authors switched to a mouse model after verifying the detection of the SERS signal from nanoparticles absorbed by the cancer cells. Injection of Tu686 cells into the flank of naked mice was performed, and strong SERS signals were visible in the resulting tumors after targeted nanoparticle injection, indicating that the probe had successfully reached the tumor, as shown in Figure 2. Meanwhile, tumors in the mice receiving injections of non-targeted nanoparticles did not exhibit any detectable SERS signal. The in vivo molecular imaging investigation of tumor biomarkers utilizing SERS was presented by the authors [86].
Fabris et al. presented a method for synthesizing a Au-nanostar (AuNS)-functionalized substrate, which can be applied for highly sensitive SERS-based sensing [87]. The AuNSs were fixed on the Au support using a Raman-silent organic tether, which allows analytes to be either chemisorbed or physisorbed on the AuNSs for sensing. The developed SERS substrate enables the quasi-quantitative and multiplexed detection and identification of analytes from mixtures. The SERS substrates can detect chemisorbed 4-mercaptobenzoic acid at a concentration as low as 10 fM with a SERS enhancement factor of 109 with high reproducibility. Most crucially, they offer a high signal-to-noise ratio when detecting physisorbed analytes, such as crystal violet [87]. Bhattacharya et al. [88] reported gold nanoflowers used as a biosensor in imaging applications. Raman signal amplification using the nanoflower (AuNf) petals is crucial for achieving signal improvements of the order of 106. The electromagnetic enhancement mechanism of metal nanoparticles can be used to explain this improvement. The toxicity of the nanostructures to the cells was evaluated in A549 human lung carcinoma cells by performing a colorimetric assay known as an MTT assay. Bamrungsap et al. [89] developed a layer-by-layer immersion technique that was used to create a plasmonic paper utilizing cellulose substrates and a composite of graphene oxide and gold nanorods (GO-AuNRs) with rhodamine 6G (R6G) was used as the probe molecule. When compared to a paper substrate coated with only AuNRs, the GO-AuNR plasmonic paper composite showed better signal intensity. The electromagnetic enhancement from the AuNRs and the chemical enhancement effect from the GO worked in concert to boost the signal. The optimal condition for developing plasmonic paper able to evaluate the highest SERS signals produced from R6G molecules was by using GO pretreatment (2 mg/mL) followed by two immersion cycles into the solution of AuNRs. The calculated enhancement factor of the plasmonic paper was reported to be 4.56 × 107, while a limit of detection of 0.1 nM R6G was achieved. The plasmonic paper was also evaluated for its ability to detect the anti-cancer medication Mitoxantrone (MTX). This straightforward and cost-effective plasmonic-paper-based SERS application is intended for trace analysis and medication monitoring.

4. Silver-Based Nanomaterials for SERS and Their Applications in Biosensing

The unique and distinctive optical properties of silver (Ag), which minimize inter-band transitions, favor plasmonic resonance and offer a high SERS enhancement factor, making silver a good SERS substrate [90]. Either chemical interactions or physical forces are used to fine-tune the AgNPs’ shape, size, and assembly. Tan et al. [91] have evaluated the beneficial use of AgNPs in clinical biosensing applications. In general, enhanced-performance modified AgNPs are proposed as biosensing platforms for conditions such as viral or bacterial infections and cancer. AgNPs are a reliable choice for improving the SERS signal and enhancing detection sensitivity. Robust SERS substrates should possess two main properties: (i) numerous “hot spots” in spaces between adjacent metal NPs, and (ii) a strong adsorption ability [92]. In this instance, a variety of hybrid nanomaterials, such as AuNPs@Q-Sepharose microsphere [93], AgNPs@polymethyl methacrylate film [94], AgNPs/agar/PAN electrospun nanofibers [95], AgNPs@graphene [96], AuNPs/WS2 nano-dome/graphene [97], and others have been developed and used as SERS-active substrates. However, the majority of these composite nanomaterials were unable to efficiently trap target molecules as they approached the surface of the metal NPs. A novel SERS biosensor based on AgNPs@MOFs capable of mimicking peroxidase was developed for the first time for blood cholesterol monitoring by Wu et al. [98]. The development of AgNPs on the surface of MOF produced hybrid AgNPs@MOF nanomaterials, which were used as the SERS substrate. A SERS biosensor for blood cholesterol detection with a limit of detection of 0.36 μM was demonstrated. Further, the sensor uses metal NPs@Fe-based MOFs, which act as both a SERS-active substrate and as a peroxidase-mimicking nanozyme. The monitoring of cholesterol with high sensitivity, specificity, and accuracy shows a significant and promising potential for a translational SERS-based blood cholesterol sensing approach [98]. Le et al. reported a SERS application based on an easy approach for developing a SERS-active substrate with a two-dimensional macroporous Ag film, which is made of silver nanosheet (AgNS)-coated inverted opal film. This substrate has good SERS reproducibility with a high enhancement factor of 6 × 107. The detection of rhodamine 6G and the detection of DNA in a label-free manner was achieved. The 2D AgNS-coated inverse opal film is a high-performance SERS-active substrate with potential for biosensing applications [99]. In 2013, Fang et al. [100] demonstrated how silver nanocubes (AgNC) self-assemble into dense bowl-shaped arrays using a polystyrene nanosphere (PSNS) template. The group discovered a facet-to-facet arrangement in most of the AgNCs and the SERS hot spot was localized to the cubes’ corners. This SERS substrate has strong amplification capability due to the densely organized AgNCs, enabling single molecule detection, which was demonstrated utilizing the bi-analyte Raman method [100]. Although SERS-based biosensing has shown significant promise in laboratory settings, its practical applicability is restricted due to the short life span of commonly used SERS-active substrates based on AgNPs. The development of a novel, cost-effective substrate made from AgNPs shielded by tiny nitrogen-doped graphene quantum dots (Ag NP@N-GQD), and its systematic evaluation for glucose sensing is an attempt at SERS-based field biosensing. The Raman amplification was significantly stronger on the new substrate in comparison to the pure Ag substrate. More significantly, unlike pure AgNPs, this substrate maintained its SERS capability for at least 30 days in a typical indoor environment, sustaining performance in both the wet and dry phases. The Ag NP@N-GQD thin film was proven to be an efficient SERS substrate for glucose detection in dried mouse blood samples details of which are mentioned in Table 2 [101].
The in-situ production of Ag colloids is another quick and highly sensitive method that in the future can be employed in point-of-care diagnostics [102,103,104]. This is gaining popularity as an adjunct approach in comparison to its widely known counterpart, which is carried out by exposing pre-made AgNPs to a biomass of bacteria, as the latter method’s limited spectrum consistency makes it challenging to probe the bacterial fingerprints. However, a direct interaction between AgNPs and the bacteria enables the acquisition of very strong SERS spectra due to the strong electrostatic attraction between the positively charged Ag ions and the negatively charged bacterial components. Most recently, induced adherence to the cell wall in cyanobacteria was also described [102,103,104,105,106]. For the simultaneous identification of multiple diseases, label-free detection uses the intrinsic SERS signals seen in cell walls. The label-free (direct) SERS-based approach is sensitive and depends heavily on the SERS substrate, and using this method in biofluids might be difficult. Additionally, the spectra of many bacterial species can be strikingly similar. Therefore, it is necessary to deploy appropriate chemometrics techniques and discrimination models.

5. Copper-Based Nanomaterials for SERS and Their Applications in Biosensing

In the visible region, metallic nanoparticles like Ag, Au, and Cu display LSPR. The two biggest drawbacks of these nanomaterials when used for SERS enhancement are their high cost and limited stability. Likewise, corrosion and oxidation are two of Copper Nanoparticles’ (CuNPs) primary drawbacks despite their low and reasonable pricing. Stable CuNPs can be made using several quick and simple chemical processes [107,108]. However, surface contamination is unavoidable when reducing agents are present. These contaminations disrupt applications that involve surfaces, like SERS, as well as those that are biological or catalytic. Copper oxide NPs are an important category of SERS substrates. In 1998, Kudelski et al. [109] reported the SERS activity of nanostructured Cu2O, making it the second metal oxide to be recognized as a SERS-active substrate [110]. Lin et al. demonstrated highly uniform cubic, rhombic dodecahedral, and octahedral Cu2O microcrystals with well-defined 100, 110, and 111 facets [111,112]. In 2019, Aghdam et al. performed a SERS experiment using spherical Cu/Cu2O core-shell NPs using pulsed laser ablation (nanosecond Ce: Nd YAG) in liquid. The SERS activity of Cu/Cu2O core-shell NP substrates was determined using crystal violet (CV) and methylene blue (MB) and a green laser (532 nm) excitation source. The high enhancement of the SERS signal from the adsorbed analyte molecule was due to the Cu core showing the LSPR effect, resulting in EE, and the Cu2O shell possessing a rough surface, resulting in chemical enhancement. Furthermore, the degree of charge transfer was assessed by determining the intensities of the fully and partially symmetric modes. This analysis showed that in the SERS of the Cu/Cu2O-CV and Cu/Cu2O-MB, the LSPR increase predominates the charge-transfer resonance contribution, with the substrates demonstrating a 28% variation in the strength of the SERS signals [113]. For biological sensing applications, the detection of bacteria with copper nanomaterials is challenging in SERS platforms. Surface-enhanced Raman spectrum of Staphylococcus aureus a bacterium found in the respiratory tract using 785 nm is shown in Figure 3 [114]. Kowalska et al. developed the platforms used to generate the spectrum shown in Figure 3. The platforms are made of copper instead of the customary, costly Au or Ag. The platforms were developed using a brand-new, straightforward, economical, and quick high-pressure approach that involves the breakdown of copper hydride. A malachite green isothiocyanate standard was used to verify the platform enhancement factors. Depending on the pressure applied, the platforms display extraordinarily high SERS enhancement factors. The computed improvement factors were discovered to be between 1.5 and 4.6 × 106, and the determined value of the average spectral correlation coefficient was 0.82. Staphylococcus aureus germs were detected using these SERS platforms, which are innovative platforms that have the potential to replace more traditional silver or gold SERS substrates as effective instruments for biological or medical diagnosis. N.E. Markina et al. reported the presence of cephalosporin antibiotics in urine samples, determined using CuNP-based SERS with a lower detection limit than using other approaches [70]. To speed up the reaction and boost the homogeneity of the CuNPs, the synthesis of the CuNPs was tuned to maximize the analytical signal. The analytes of interest were ceftriaxone (CTR), cefazolin (CZL), and cefoperazone (CPR). The determination tests were conducted on samples of actual human urine that had been intentionally contaminated with substances at levels that corresponded to therapeutic drug monitoring (TDM) limits (50–500 μg mL−1). The universality of the suggested technique was ensured by performing sample dilution as a pretreatment. The minimum concentrations needed for TDM were all below the limits of detection, which were 7.5 (CTR), 8.8 (CZL), and 36 (CPR) μg mL−1. CuNPs showed a competitively high Raman enhancement efficiency (for excitation at 638 nm) compared to Ag and Au nanoparticles.
For real-world SERS applications, Cu chips are more cost-effective compared to Ag and Au chips, but the poor stability and weak SERS of Cu substrates are a big concern. Dai et al. reported a process to develop Cu-based SERS chips that are highly sensitive as well as stable [115]. The Cu-coated fabric was used as a SERS chip to detect crystal violet with LOD as low as 10−8 and an enhancement factor of 2.0 × 106 M. Furthermore, the Cu membrane on the fabric, which is hydrophobic, also plays an important role by reducing background noise and providing stability. After air storage of nearly 2 months, the chip’s SERS intensity decreased to 18% of its initial level. A replacement reaction was used to introduce Ag onto the pristine Cu surface to improve the SERS performance of the Cu chips. The Ag-modified Cu chips showed a better enhancement factor of 7.6 × 106 and a three-orders-of-magnitude reduction in the LOD of CV to 10−11 M. This occurred due to the plasmonic coupling between Cu and Ag at the nanoscale. The SERS intensity of the Cu–Ag chip maintained 80% of its initial intensity after two months of storage because of the additional protection provided by the Ag shell [115].

6. Bimetallic Nanomaterials for SERS and Their Applications in Biosensing

The enhancement of SERS signal efficiency and reproducibility can be achieved by improving and developing effective substrates. As SERS is a phenomenon based on resonance, excitation condition matters [116]. Unlike monometallic nanoparticles (MNPs) such as gold, silver, copper, and others, as shown in Figure 4, bimetallic nanoparticles (BMNPs) are nanoparticles with two different metal elements such as gold–silver (Au–Ag), silver–copper (Ag–Cu), or gold–palladium (Au–Pd). Due to the presence of two metal elements, such nanoparticles possess better stability and better tunable plasmonic properties, which results in an enhanced SERS signal compared to their single-metal counterparts [2]. Liu et al. reported that, compared to the conventionally used AuNP substrates, nanoporous bimetallic gold and palladium nanostructures showed an enhanced SERS signal [117]. Two kinds of bimetallic nanoparticles are used to develop SERS substrates namely, alloyed nanoparticles and core–shell nanoparticles. In alloyed bimetallic nanoparticles, two metal atoms are homogenously mixed, resulting in the presence of both metals on the surface of the BMNPs. At room temperature, Au–Ag alloyed BMNPs have high spin electron relaxation, making them an effective substrate for room-temperature-based biosensing applications. Furthermore, Au–Ag alloys provide a significant increase in sensitivity, as this alloy is of lower density, increasing the signal-to-noise ratio and providing thermal and chemical stability. Conversely, the core–shell bimetallic configuration consists of one metal at the core and another metal surrounding the core known as the shell. The synthesis of core–shell BMNPs involves the synthesis of the core followed by the development of the shell. Au–Ag core–shell BMNPs of different shapes, such as spherical, cuboidal, and dumbbell-shaped, have been widely explored as SERS substrates, showing enhanced signal intensity [2,29,117,118]. Among Ag and Au, the plasmonic efficiency of Ag is higher, whereas the chemical stability of Au is higher. Studies have demonstrated that NPs made of either Au or Ag have lower SERS activity compared to Au–Ag BMNPs [117,119,120,121,122,123,124]. To synthesize the spherical Au–Ag BMNPs, the co-reduction method is commonly used in which Ag+ and Au3+ ions are reduced simultaneously. As reported earlier, this method has also been used for developing other nanostructures with rod, wire, and triangular shapes. Furthermore, for developing mostly hollow alloy Ag–Au BMNPs, the galvanic replacement method by controlling reaction time is used, which is based on the reduction potential of Au3+ and Ag+. BMNPs also combine the potentials of both metals in terms of their chemical and plasmonic properties relative to pure metals [2,85,125,126]. This also indicates that the chemical nature of the metals should also be considered when developing SERS substrates. Pinholes present in the Au nanoshell’s surface act as hot spots for SERS by enhancing the local electric field [127]. This electric field amplifies the Raman signal. Mucin-1, a breast-cancer-specific protein biomarker, was detected with a detection limit of 4.3 aM using BMNPs, as shown in Figure 4D–F. Moreover, the presence of Mucin-1 decreases the hotspots by separating the aptamers and their complementary strands, leading to a reduction in the SERS signal [128,129].
A SERS-based immune assay has been developed with high sensitivity to diagnose Hepatitis B virus in human blood plasma using an active SERS substrate on an antibody-carrying microfluidic chip [29,130,131]. Influenza A virus detection was achieved using a multilayered Au–Ag-SERS-substrate-based immune sensor [132]. Cao et al. reported that Au–Ag core–shell BMNPs enable highly sensitive and multiplexed detection of oligonucleotides captured on a microarray chip. They further demonstrated a capability to distinguish six dissimilar DNA targets with six Raman-labelled nanoparticles and two RNA targets with single nucleotide polymorphism with a detection limit on the 20 femtomolar scale [133]. Au-Ag-BMNP-nanowire-substrate-based SERS was used for the rapid detection of lung-cancer-related microRNA (mi-196a) by coupling it with hairpin DNA. Raman signals were enhanced by creating hot spots between the Ag nanowires and AuNPs. This method of detection was presented as an possible alternative to conventional techniques for microRNA detection i.e., RT-PCR (real-time polymerase chain reaction), with detection limits of 96.58 aM in the PBS and 130 aM in the serum, respectively [134]. Highly reproducible detection and discrimination with low power and short acquisition time of three bacteria, Escherichia coli, Salmonella typhimurium, and Bacillus subtilis was demonstrated using SERS and a Ag–Au BMNP substrate [135]. Other transition metals such as platinum, palladium, rhodium, ruthenium, cobalt, and nickel-coated Au core have also been reported [2].

7. Conclusions and Perspective

In this review, we have described the principles of SERS and different metallic nanoparticles and their application in the biological domain. The SERS technique has been widely explored and applied in many fields such as biomedical, drug and pharmaceutical, molecular, microbiological, and other research fields. SERS combines Raman spectroscopy with nanotechnology, turning it into a remarkable optoelectronics biosensor due to its fast detection with higher sensitivity. The goal of SERS-based biosensing is to improve the limit of detection. SERS probes have poor stability with respect to temperature fluctuations, making them of limited suitability. Storage is also an issue, as long-term storage makes the NPs susceptible to agglomeration. However, stability can be increased using encapsulation by polymers. Plasmonic metals are better in terms of SERS signal compared to semiconducting and dielectric materials but lag behind in terms of stability and storage. Challenges in terms of SERS-based biosensors come with developing highly sensitive and reusable SERS substrates. Many biosensing applications have already been developed and reported, but they still lack commercialization. The reproducibility of SERS substrates requires more improvement as their performance with narrow plasmons is influenced by even slight changes in the nanostructure, which leads to a significant LSPR shift. SERS-based biosensing also suffers from the presence of background molecules or impurities along with the biomolecule of interest in the physiological environment. Therefore, in terms of practical applications, much improvement is required. Optimization of sample preparation strategies is very crucial to SERS-based biosensing to ensure that the biomolecule of interest has a preference for the SERS-active substrate, minimizing the competition for binding sites and increasing the sensitivity. The conventional approach is monitoring and adjusting pH, ionic strength, dilution, and surface modification. Combining SERS biosensing with advanced chemometrics and machine learning algorithms for processing is one of the feasible approaches for determining the SERS signal of interest. For SERS-based intra-cellular biomolecule dynamic biosensing, the stability and toxicity of the SERS probe need to be extensively optimized and critically evaluated to understand biocompatibility. For analyzing the biocompatibility and choosing the SERS substrate, it is always better to analyze the size and chemical structure of the analyte and matrix complexity. The key factor influencing the optical setup of a SERS biosensor for analyte detection is the excitation source wavelength, which is highly dependent on the choice of metallic nanomaterial. For instance, the resonance frequency of silver nanoparticles is blue-shifted compared to a similar nanoparticle made of gold nanoparticles. Furthermore, the enhancement factor of the SERS signal is highly influenced by the shape and size of the colloidal metal nanoparticles. Therefore, different advanced strategies for improving SERS-based biosensing for both qualitative and quantitative analysis in the fields of bioimaging, disease diagnosis, microbiology, and molecular biology should be the focus of future research. Another limitation is the masking of the SERS signal by fluorescence, which has been mostly dealt with by the use of confocal SERS, an NIR excitation source, or quenching of the source of the fluorescence by metallic nanoparticles. Furthermore, Raman spectrometer instrumentation cost and the need for sophisticated instruments also limit SERS biosensor applicability. Rapid detection and diagnosis along with lower detection limits are one research interest in the biomedical field and must be improved for translation. In aiming for translation, the development of easy-to-use hardware and software, alongside higher sensitivity, selectivity, reproducibility, and cost-effective approaches, needs to be actively kept in mind. Further qualitative and quantitative multiplex analysis of biomolecules or analytes in complex mixture solutions can be the next step towards advanced in situ biosensing applications. SERS-based biosensing has promising potential with the developments in plasmonic nanoparticles and different machine-learning tools. The development of low-cost, easily operated, and miniaturized smart SERS biosensors could lead to these becoming point-of-care testing tools in the future.

Author Contributions

J.K.: outline, editing the original draft, writing—Abstract Introduction, Bimetallic nanoparticles for SERS and applications in biosensing, conclusion and perspective; S.S.R.: writing—Gold/Silver/Copper-based Nanomaterials for SERS and application in biosensing; M.S.P.: editing and reviewing the original draft. A.V.: editing and reviewing the original draft; S.P.S.: supervision, outline, writing and editing the original manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. (A) Metal nanoparticles showing localized surface plasmon resonance when exposed to Electromagnetic waves of the specific wavelength resonating with plasmon frequency. (B) Spontaneous Raman Scattering and Surface-enhanced Raman scattering. (C) Electromagnetic enhancement of SERS signal (D). Chemical enhancement of SERS Signal due to SERS substrate and analyte complex formation. (Adapted from Refs. [2,7]).
Figure 1. (A) Metal nanoparticles showing localized surface plasmon resonance when exposed to Electromagnetic waves of the specific wavelength resonating with plasmon frequency. (B) Spontaneous Raman Scattering and Surface-enhanced Raman scattering. (C) Electromagnetic enhancement of SERS signal (D). Chemical enhancement of SERS Signal due to SERS substrate and analyte complex formation. (Adapted from Refs. [2,7]).
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Figure 2. ScFv-antibody-conjugated gold nanoparticles for tumor biomarker EGFR detection. In vivo SERS spectra from tumor site (red) and liver locations (blue) using (A) targeted and (B) nontargeted gold nanoparticles. Malachite green, which has unique spectral signatures, is the Raman reporter molecule and is indicated in (A,B). (C) Images of 785 nm laser beam (laser power = 20 mW) focused on the liver’s anatomical location and tumor’s site. The liver site (blue) and the tumor site (red) were used to obtain in vivo SERS spectra using 2 s signal integration and 785 nm excitation. (Adapted with permission from Ref. [86]. Copyright 2007, Springer Nature).
Figure 2. ScFv-antibody-conjugated gold nanoparticles for tumor biomarker EGFR detection. In vivo SERS spectra from tumor site (red) and liver locations (blue) using (A) targeted and (B) nontargeted gold nanoparticles. Malachite green, which has unique spectral signatures, is the Raman reporter molecule and is indicated in (A,B). (C) Images of 785 nm laser beam (laser power = 20 mW) focused on the liver’s anatomical location and tumor’s site. The liver site (blue) and the tumor site (red) were used to obtain in vivo SERS spectra using 2 s signal integration and 785 nm excitation. (Adapted with permission from Ref. [86]. Copyright 2007, Springer Nature).
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Figure 3. SERS spectrum of Staphylococcus aureus using novel highly sensitive Cu-based SERS platforms. (Adapted with permission from the Ref. [114]. Copyright 2015, John Wiley and Sons).
Figure 3. SERS spectrum of Staphylococcus aureus using novel highly sensitive Cu-based SERS platforms. (Adapted with permission from the Ref. [114]. Copyright 2015, John Wiley and Sons).
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Figure 4. Schematic representation of (A) Two different monometallic nanoparticles represented as yellow and green. (B) Alloy BMNP substrate surface. (C) Core (yellow) shell (green) BMNPs. (D) Detection of mucin1 via SERS with bimetallic gold nanorod core and AgNP satellite assemblies. (E) Enhanced SERS spectra of Mucin 1. (F) Peak intensity at 1142 cm−1 for Mucin-1 detection with detection limit of 4.3 aM. (D–F are adapted with permission from [128,129]. Copyright 2015, Royal Society of Chemistry).
Figure 4. Schematic representation of (A) Two different monometallic nanoparticles represented as yellow and green. (B) Alloy BMNP substrate surface. (C) Core (yellow) shell (green) BMNPs. (D) Detection of mucin1 via SERS with bimetallic gold nanorod core and AgNP satellite assemblies. (E) Enhanced SERS spectra of Mucin 1. (F) Peak intensity at 1142 cm−1 for Mucin-1 detection with detection limit of 4.3 aM. (D–F are adapted with permission from [128,129]. Copyright 2015, Royal Society of Chemistry).
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Table 1. SERS-based biosensing applications of metallic nanomaterials.
Table 1. SERS-based biosensing applications of metallic nanomaterials.
Metallic NanomaterialsApplicationsRef.
GoldDetection of calcium mobilizing second messenger nicotinic adenine dinucleotide phosphate (100 µM) in cell extract without sample purification and labeling.[55]
Label-free multiplex detection of miRNAs; miR– 10b, miR–21, and miR–373 relevant to cancer metastasis with LODs of 3.53 fM, 2.17 fM, and 2.16 fM.[56]
Ultrasensitive and selective detection of Alzheimer’s Tau protein using SERS-based sandwich assay.[57]
Quantitative multiplex sensing of DNAs with a limit of detection of 10 pM.[58]
Sensing of bacterial endotoxin (lipopolysaccharide) with the low detection limit of 5 lipopolysaccharide molecules per AuNP.[59]
SERS-based onsite detection of breast cancer using human tears and detection at femtomole scale[60]
Label-free sensing of quinoline antibiotic found in wastewater with a 5.01 ppb lower limit of detection.[61]
Drug (doxorubicin) biosensing in biological fluid using SERS. The experimental limit of detection in water is 1 nM and in human and bovine serum is 16 nM.[62]
SARS-CoV-2 detection using the SERS platform with a limit of detection of virus concentrations less than 10 PFU/ml.[63]
SilverDetection of amyloid-β (a known hallmark for Alzheimer’s disease pathogenesis) peptide aggregates in biological fluids with a nanomolar limit of detection using AgNP composite SERS sensors and a 532 nm laser.[64]
SERS biosensing and drug delivery of anticancerous doxorubicin using nanosized graphene-oxide-coated AgNPs.[65]
Label-free identification of circulating cancer protein biomarkers. Using SERS active strip natural diatomite coated with AgNPs via a layer-by-layer assembly method.[66]
Quantitative rapid SERS detection of Bacillus cereus spore biomarker 2,6-pyridine dicarboxylic acid with a limit of detection as 8.62 nM.[67]
Quantitative detection of tenofovir down to 25 ng/ml clinically relevant concentrations in an aqueous matrix using SERS.[68]
Detection of esophageal cancer using stable and low-toxicity polyethylene-glycol-coated silver nanocubes.[69]
CopperSERS-based determination of cephalosporins antibiotics in spiked human urine using CuNPs.[70]
SERS detection of designer drugs using copper nanowires coated carbon fibers.[71]
SERS-based sensitive detection of telomerase activity using copper oxide nanoparticles.[72]
BimetallicHighly reproducible and accurate single-cell Raman imaging and in vivo tumor imaging with 1 × 1 mm2 area can be quickly achieved within 35 s under open-air conditions using SERS Au core–Raman-active molecule–Ag shell–Au shell nanoparticles.[73]
Au/Ag core–shell nanoparticles, conjugated with monoclonal antibodies for highly sensitive SERS imaging of cancer biomarkers in live cells.[74]
Sensitive detection of Anticancer drug mitoxantrone using Bimetallic Ag–Au and Ag–Cu alloy microflowers SERS sensor with a limit of detection of 1 fM.[75]
Table 2. Detection of glucose and different parameters for cost analysis for SERS techniques with silver nanoparticles. Analysis of itemized cost for synthesizing 5 mg Ag NP@N-GQD, which requires 0.8 mg N-GQD and 10 mg AgNO3. The measured baseline glucose level (diluted by 10 times) is 0.21 mM. The first and second values in the column “Estimated increase in glucose concentration” give the mean value and the standard deviation, respectively. Note that the Mean Percent Error is calculated as (ΔEstimated − ΔExpected)/ΔExpected × 100%, where ΔEstimated represents the mean estimated increase in glucose concentration and ΔExpected represents the expected increase in glucose concentration. (Adapted from Ref. [101]).
Table 2. Detection of glucose and different parameters for cost analysis for SERS techniques with silver nanoparticles. Analysis of itemized cost for synthesizing 5 mg Ag NP@N-GQD, which requires 0.8 mg N-GQD and 10 mg AgNO3. The measured baseline glucose level (diluted by 10 times) is 0.21 mM. The first and second values in the column “Estimated increase in glucose concentration” give the mean value and the standard deviation, respectively. Note that the Mean Percent Error is calculated as (ΔEstimated − ΔExpected)/ΔExpected × 100%, where ΔEstimated represents the mean estimated increase in glucose concentration and ΔExpected represents the expected increase in glucose concentration. (Adapted from Ref. [101]).
ComponentChemical AgentACS NumberPack SizePrice (USD)Chemical Quantity for Synthesizing 5 mg Ag NP@N-GQDCost (USD)Cost Distribution
Ag NPAgNO37761-88-85 g24.910.0 mg4.98 × 10−299.67%
N-GQDCitric Acid77-92-9500 g90.30.8 mg1.45 × 10−40.29%
Dicyandiamid461-58-51000 g45.70.4 mg1.83 × 10−50.04%
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Karlo, J.; Razi, S.S.; Phaneeswar, M.S.; Vijay, A.; Singh, S.P. Metallic Nanoparticles for Surface-Enhanced Raman Scattering Based Biosensing Applications. Photochem 2024, 4, 417-433. https://doi.org/10.3390/photochem4040026

AMA Style

Karlo J, Razi SS, Phaneeswar MS, Vijay A, Singh SP. Metallic Nanoparticles for Surface-Enhanced Raman Scattering Based Biosensing Applications. Photochem. 2024; 4(4):417-433. https://doi.org/10.3390/photochem4040026

Chicago/Turabian Style

Karlo, Jiro, Syed S. Razi, Mahamkali Sri Phaneeswar, Arunsree Vijay, and Surya Pratap Singh. 2024. "Metallic Nanoparticles for Surface-Enhanced Raman Scattering Based Biosensing Applications" Photochem 4, no. 4: 417-433. https://doi.org/10.3390/photochem4040026

APA Style

Karlo, J., Razi, S. S., Phaneeswar, M. S., Vijay, A., & Singh, S. P. (2024). Metallic Nanoparticles for Surface-Enhanced Raman Scattering Based Biosensing Applications. Photochem, 4(4), 417-433. https://doi.org/10.3390/photochem4040026

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