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Review

Recent Strategies for MicroRNA Detection: A Comprehensive Review of SERS-Based Nanobiosensors

by
Sang Baek Sim
1,
Izzati Haizan
2,
Min Yu Choi
1,
Yubeen Lee
1 and
Jin-Ha Choi
1,2,*
1
School of Chemical Engineering, Clean Energy Research Center, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si 54896, Jeonbuk State, Republic of Korea
2
Department of Bioprocess Engineering, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si 54896, Jeonbuk State, Republic of Korea
*
Author to whom correspondence should be addressed.
Chemosensors 2024, 12(8), 154; https://doi.org/10.3390/chemosensors12080154
Submission received: 26 June 2024 / Revised: 18 July 2024 / Accepted: 2 August 2024 / Published: 6 August 2024
(This article belongs to the Special Issue Chemosensors in Biological Challenges, Volume II)
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Abstract

:
With advances in technology, diagnostic techniques have become more sophisticated and efficient at detecting biomarkers rapidly. Biomarkers such as microRNA (miRNA), which exhibit exceptional specificity and sensitivity compared with other biomarkers, have garnered particular interest. Composed of 21–24 nucleotides, miRNAs constitute a noncoding RNA group that regulates gene expression, immune system activation, apoptosis, and other cellular processes; hence, they are frequently used as biomarkers for various diseases. This has sparked significant interest regarding the identification of the specific miRNAs implicated in many diseases. Presently, miRNA detection methods include northern blots, reverse transcription-quantitative polymerase chain reaction, and next-generation sequencing. While these methods are all sensitive, they are time-consuming, complex, and expensive, which renders them unsuitable for on-site detection. Surface-enhanced Raman scattering (SERS) can overcome these limitations to enable the sensitive and rapid detection of miRNA. This technique amplifies Raman signals, with signal enhancement levels changing sensitively depending on the distance between the target molecule and substrate. Therefore, this review covers the principle of SERS as a method for detecting miRNAs using nanomaterials, along with examples of nanomaterials and SERS applications. Based on the available literature, SERS is anticipated to enable the convenient, early diagnosis of various diseases, potentially lowering mortality rates. This review could therefore contribute significantly to the advancement of medical and diagnostic technologies.

1. Introduction

Technological advancements have enabled refinements to diagnostic methodologies to enhance their sensitivity, speed, and specificity in detecting biomarkers. Notably, within the field of biomarkers, microRNAs (miRNAs) have emerged as particularly promising candidates, supported by extensive research validating their significant associations with both health and disease states. miRNAs are a group of noncoding RNAs consisting of 21–24 nucleotides. They are involved in regulating transcription and expression, modulating the immune system, and playing substantial roles in cellular apoptosis [1,2,3]. Thus, miRNA is strictly regulated within the body, and in the expression of various diseases, miRNA can be dysregulated or non-specifically expressed. The miRNAs associated with cancer include miRNA-451a, miRNA-155, miRNA-125, and miRNA-224, which indicate lung cancer, breast cancer, colorectal cancer, and liver cancer, respectively [4]. Furthermore, miRNA-146b and miRNA-15b are utilized as biomarkers for Alzheimer’s disease, a neurodegenerative disorder, while miRNA-23 and miRNA-133 are employed as biomarkers for cardiovascular diseases [2,5,6].
Advancements in miRNA detection methods have resulted in the emergence of various technologies, such as northern blots, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and next-generation sequencing (NGS). Among these, northern blots represent the most classical method for detecting miRNA, involving the extraction of miRNA from samples, followed by size-based separation via gel electrophoresis [7,8,9,10,11]. However, this technology is complex and time-consuming, lacks multiplex detection capabilities, and relies on mass-based measurements; thus, it cannot differentiate between RNA molecules with the same mass but different nucleotide sequences, which constitutes a critical drawback [12]. These drawbacks can be addressed by RT-qPCR. The most significant difference between RT-qPCR and northern blots is the capability for quantitative analysis [13]. The process of RT-qPCR involves reverse transcription to generate complementary DNA (cDNA) strands from the target miRNA, followed by PCR amplification [8]. The amount of cDNA produced during the reverse transcription process varies depending on the quantity of the target miRNA, which enables quantitative analysis [8]. The resulting cDNA serves as a template for PCR amplification, which can be monitored in real time using fluorescent dyes [14]. Although this method is sensitive, it involves complex and time-consuming procedures. NGS involves analyzing genetic information after fragmenting the genome into multiple pieces and sequencing them simultaneously. Compared with traditional methods such as northern blots and RT-qPCR, which require prior knowledge of genetic information for detection, NGS allows for relatively rapid analysis and the discovery of new genetic information [8,15]. However, while this approach is excellent for reading vast amounts of genetic information, its drawbacks include its complex processes, data processing, and expensive equipment [12,16].
Various technologies are being developed to compensate for these shortcomings, and the foremost among them is based on Raman spectroscopy. Because each substance has a specific signal, Raman scattering can be used to analyze different substances; however, this method may become ineffective if the signal is too weak. Surface-enhanced Raman scattering (SERS) is a technology that amplifies Raman signals from molecules, and Raman signals are amplified when molecules are attached to substances such as metals; moreover, as SERS is highly sensitive to distance, it can detect miRNA more easily and sensitively [17]. Therefore, in this review, we describe SERS with nanomaterials as a method that can address the limitations of the aforementioned techniques and provide a solution suitable for point-of-care testing. Additionally, we explore various applications of SERS. This technique has the potential to provide significant assistance in areas with inadequate medical facilities, enabling swift medical care. SERS is anticipated to have a substantial impact in the fields of medical technology and diagnostic techniques.

2. SERS

Raman scattering occurs when light is scattered by a substance, resulting in different wavelengths due to vibrational motion within the substance, known as the Stokes shift. While most incident light is reflected at the original wavelength due to Rayleigh scattering, some light undergoes Raman scattering with shifted wavelengths [18]. The Raman signal is the fingerprint of a molecule, as it is uniquely associated with the specific components of that molecule.
SERS is a technique that amplifies the Raman signals produced when Raman scattering from a substance is enhanced near a nanometal surface. This technology is widely used for the rapid, nondestructive detection of low concentrations of substances, as it is highly sensitive to distance [19].
The principles of SERS are primarily governed by two mechanisms: chemical and electromagnetic [20]. The electromagnetic mechanism involves the enhancement of Raman signals by a strong electric field formed near nanometal particles due to surface plasmon resonance [21]. The chemical mechanism involves the enhancement of Raman scattering through chemical interactions between the substance and the nanometal surface [22].
The chemical mechanism is based on the interactions between the metal surface and molecules. When molecules adhere to the metal surface, Raman signals are amplified due to the resonance induced by charge transfer and vibrations [23,24]. The attached molecules vibrate, forming a complex between the molecule and the metal. In this complex, electrons are exchanged between the highest occupied molecular orbital or lowest unoccupied molecular orbital of the molecule and the Fermi level of the plasmon [25,26]. When the energy level matches the wavelength of the laser, resonance occurs, leading to the generation of SERS signals; the Raman signal is thus amplified [27]. CM amplifies the Raman signal by approximately 100 to 1000 times [28]. To augment the aforementioned chemical enhancement (CM) effects, various SERS substrates such as MXene and graphene oxide (GO) have been investigated. Detailed discussions on SERS substrates are provided in subsequent sections.
The electromagnetic mechanism mentioned earlier is based on the interaction between light and nanometal surfaces, as well as substances adsorbed on the surface (Figure 1) [17,29,30]. This mechanism involves a significant amplification of Raman signals at certain points, enhancing the signal by approximately 1010 to 1011 times where the intensity of the electromagnetic field increases dramatically due to surface plasmon resonance; these points are called “hotspots” [28,31]. The plasmonic effect typically occurs when light is incident on nanostructures with wavelengths shorter than those of the material, which induces surface electromagnetic waves through the interaction of free electrons around metal particles with light [32]. These surface electromagnetic waves are reinforced through interactions with substances adsorbed on the surface, which strengthens the electric field and amplifies the Raman signals. When the resonant frequency of the metal aligns with the wavelength of the incident light, the plasmonic effect is intensified further, creating a strong magnetic field that enhances the electromagnetic mechanism [33,34]. In SERS, the resonance frequencies of the rough surfaces of commonly used metals, such as gold (Au) and silver (Ag), typically align closely with the wavelengths of visible light. This similarity allows for a more accurate measurement of Raman signals than when using other metals [35].
In the SERS platform, one of the main challenges is to achieve a reproducible and accurate quantification of results [36]. Specifically, uneven molecule coverage and variable binding interactions can lead to inconsistent SERS signals that affect both the reproducibility of results and the proper quantification of analytes [37]. With the increasing interest in SERS, more research is focusing on CM and electromagnetic enhancement (EM) by uniformly fabricating molecule coverage and ensure stable binding dynamics [38]. As EM contributes more to SERS than CM does, efforts have been made to enhance hotspots in order to achieve more effective SERS [26,39]. Hotspots are regions with extremely enhanced magnetic field strength arising from the surface plasmon resonance that occurs when light is incident on nanostructures. In these intensified magnetic fields, signals and radiation are amplified [27]. Hence, various forms of Ag@Au and SERS tags have been developed to amplify hotspots, which are discussed in detail in the next section [17].

3. SERS Materials for Biomarker Detection

3.1. Noble Metal Materials

SERS is a spectroscopic technique based on the surface plasmon resonance phenomenon that amplifies the vibrational frequencies of molecules. SERS is significantly influenced by the interaction between adsorbed molecules and the surface of plasmonic nanostructures [38,40] Au and Ag are commonly utilized in SERS research, as they exhibit plasmon resonance in both the visible-light and near-infrared regions due to their optical properties [41,42,43]. A detailed description of the nobel metal materials used in SERS is presented (Table 1).

3.1.1. Gold (Au)

Au, one of the representative noble metals, is widely utilized in biosensing technology due to its biocompatibility, tunability, and nontoxic nature [44,45].Additionally, Au is often used at the nano scale in detection systems associated with SERS [46], as its branched morphology enables the facile generation of structural hotspots. The creation of hotspots plays a pivotal role in SERS [47]. Depending on the composition, size, and aggregation states, the shape and geometry of the nanostructure can be controlled closely [48,49].
Conventional SERS substrates have predominantly comprised colloidal solutions in which Au or Ag nanoparticles (NPs) are randomly dispersed. However, this results in a random distribution of hotspots, uneven adsorption onto targets, poor reproducibility, and high steric hindrance. Recent studies have demonstrated that self-assembled arrays of AuNPs at liquid–liquid interfaces are easy to fabricate, exhibit orderly stability, and ensure a uniform distribution of hotspots, thereby serving as ideal SERS substrates and overcoming the aforementioned limitations [50]. When generating uniform hot spots using ordered arrays, the optimization of parameters such as the interparticle distance and nanoparticle diameter is required to achieve more efficient SERS signals [51]. In this section, we focus on studies that utilized Au to generate dense and uniform hotspots for enhancing SERS signals.
Tan et al. reported a dual-signal SERS biosensor for detecting breast cancer–related miRNA, i.e., miRNA-21 [50]. This biosensor utilizes a tightly ordered spindle-shaped gold (SAu) array with 5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) molecules (Figure 2a). They coupled a hairpin-structured DNA labeled with rhodamine X (ROX) at one end to the SAu array. The SERS signal of the ROX was weakened in the presence of the target, turning on the DNA; by contrast, the SERS signal of the DTNB remained stable. As a substrate, the Au array provided a broad range of hotspots. Based on the fact that each substance has a unique Raman peak, the researchers achieved dual-signal SERS for a single target; this resulted in low background signals, minimal detection errors, and the ability for self-calibration, thereby enabling more accurate miRNA detection. They demonstrated sensitive detection of the target in the range of 10−1 to 105 pM without any signal amplification strategy, with a limit of detection (LOD) of 0.046 pM.
Choi et al. developed a CRISPR-Cas12a-based nucleic acid amplification-free biosensor using a SERS-assisted detection system [48] This system is composed of GO/periodic triangle Au nanoflower (TANF) arrays connected to Raman probe-functionalized AuNPs via DNA. The microsized triangles and nanosized flower-shaped structures are designed to concentrate surface electrons, enhancing the Raman signal on their surfaces (Figure 2b). In the absence of the target, the Raman probe attached to the single-stranded DNA (ssDNA), designed to an appropriate length, also generated strong Raman signals, creating hotspots. In the presence of the target, the ssDNA was cleaved by the Cas protein, causing the Raman probe to move away from the array; this weakened the Raman signal, enabling target detection based on changes in signal strength. The researchers successfully multiplexed the detection of multiviral DNAs, such as hepatitis B virus, human papillomavirus 16, and human papillomavirus 18. The target detection achievable within 20 min ranged from 1 aM to 100 pM.
Wu et al. developed a sandwich-type SERS-based biosensor. This system is composed of SERS tags and a magnetic capture substrate [52]. The SERS tag consists of fractal Au NPs (F-AuNPs), and three different Raman reporters (Rhodamine 6G; R6G, Crystal violet; CV, 4-aminothiophenol; 4-ATP) are used to detect three different hepatocellular carcinoma–related microRNA targets (miRNA-122, miRNA-223, and miRNA-21). The rough surface of the F-AuNPs exhibited numerous nanogaps, and these external nanogaps formed electromagnetic hotspots, enhancing the SERS intensity. In this system, the linear range for single-target detection was 1 fM to 10 nM; moreover, multiplex detection of three targets was possible, and the system was validated with human serum samples.

3.1.2. Silver (Ag)

In SERS, AgNPs are generally more sensitive than AuNPs and are capable of generating stronger surface plasmon resonance. Ag is the most effective material due to its d-s band gap in the ultraviolet region, which does not dampen the plasmon band strongly, unlike the case of Au. Additionally, AgNPs are much more effective than their Au counterparts due to their ability to exhibit much stronger surface electric fields in the plasmon resonance state [39]. In this section, we discuss the characteristics of Ag and its impact on SERS analysis. Zhang et al. investigated a metal–semiconductor-based SERS system using Ag (Figure 3a). They explored the charge transfer effect on SERS in a semiconductor–molecule–metal system composed of Ag NPs, 4-mercaptobenzoic acid (MBA) molecules, and atomic-level TiO2 [53].
SERS is an ultra-sensitive method capable of detecting single molecules and has therefore been used in studies analyzing miRNA for early cancer diagnosis. Song et al. employed SERS for early cancer diagnosis through the simultaneous detection of miRNAs indicating various cancers using Ag nanorod (AgNR) arrays (Figure 3b). Three miRNAs related to lung cancer (miRNA-21, miRNA-486, and miRNA-375) were simultaneously analyzed using SERS sensor arrays. The detection limits of the three miRNAs in human serum were confirmed to be 393 aM, 176 aM, and 144 aM, respectively [54].
However, achieving repeatable and stable SERS detection, which requires the production of uniform AgNPs, remains a significant challenge [55]. Various studies have leveraged the characteristics of Ag to create highly sensitive biosensors by integrating Ag with other metals. Song et al. investigated and validated the performance of Au@AgPt NPs in real-time on-site monitoring of catalytic reactions based on SERS. Through the selective deposition of Ag mediated by platinum (Pt) at controlled temperatures, they fabricated Au@AgPt NPs possessing a cubic Au core and enhanced catalytic activity along with excellent SERS activity, attributed to the AgPt alloy shell. The presence of the Ag shell was shown to be essential for the growth of Pt on the cubic AuNPs (Au HNPs) [56].
Ag possesses potent antimicrobial properties, leading to its widespread utilization in various medical and commercial applications such as medical devices, wound healing, and surgical materials. However, considering its exceptional antimicrobial efficacy and long-lasting characteristics, caution should be exercised when using Ag in SERS techniques for bacterial detection [57]. Moreover, due to its toxicity, increased usage of Ag may pose threats to human health [58,59]. Dabrowska-Bouta et al. investigated the neurotoxic effects of low-dose AgNPs on brain myelin. Exposure of animals to 10 nm AgNPs at 0.2 mg/kgbw for 2 weeks resulted in enhanced lipid peroxidation and reduced concentrations of protein and nonprotein –SH groups in the myelin membrane. These findings demonstrate the impact of Ag on oxidative stress in the myelin membrane [60].
Ag also has a strong tendency to oxidize, which may impair its SERS performance [61]. This has been proven by Matikainen et al., who investigated the influence of oxidation and atmospheric carbon pollution on SERS intensity. For AgNPs, the signal intensity was observed to decrease by 20% after exposure to air for 10 min [62]. Han et al. demonstrated that exposure of AgNPs to ozone at 20 ppm leads to the formation of silver oxide (Ag2O) and a tenfold reduction in the SERS enhancement factor [63].
Zou et al. discussed various fabrication approaches for developing efficient SERS platforms using AuNR and AgNR oxide hybrids. While oxide coatings protect AgNRs, they simultaneously increase the distance between the plasmonic active materials and the analytes, which may limit the EM for the analytes. To amplify the Raman signals of analytes effectively within a few nanometers from the plasmonic active materials and thereby achieve excellent SERS performance, precise control of the oxide coating thickness is necessary. Common methods for achieving controllable oxide thickness include sol–gel and atomic layer deposition techniques [64].
Considering the aforementioned characteristics of Ag, SERS detection methods must utilize Ag in a manner that leverages its benefits while minimizing potential risks to the environment and human health.

3.1.3. Core–Shell

Continued advancements in SERS research have resulted in efforts to overcome the limitations of NPs composed of a single metal [65,66,67]. Consequently, diverse forms of NPs with two or more metals have been developed. Specifically, NPs with a core–shell structure have an internal core and an external shell. These multi-layered NPs are prepared by growing different metals onto single-metal NPs. Various forms of NPs can be fabricated depending on the type of metal, thickness, and shape of the shell; such NPs provide enhanced hotspots and thus enable effective SERS [68,69]. Moreover, multi-layered structures incur reduced costs as they require smaller amounts of precious metals. Additionally, they provide stronger plasmonic resonance than the resonance between single metals and light, which leads to superior SERS [39].
Gold Core–Silver Shell (Au@Ag)
Au and Ag are widely recognized SERS materials and are extensively employed in optical sensing. While Ag demonstrates excellent SERS signal generation, its application is restricted due to its toxicity. Conversely, Au is broadly utilized in biological detection due to its intrinsic biocompatibility. However, in terms of SERS signal generation, Au is less effective than Ag. To combine the benefits of both metals, gold core–silver shell (Au@Ag) nanostructures have been developed [39,70,71].
Furthermore, the Au@Ag core–shell configuration has evolved into various forms, such as Au@Ag nanostars, which provide enhanced hotspots. To prepare such nanostars, the mechanism of coating Au onto AgNPs is similar to that for Au@Ag core–shells, but the coating process is altered. The distinctive feature of nanostars is the simultaneous exposure of Ag cores and Au branches, with the latter providing intensified hotspots [69,70]. Peng et al. researched a highly sensitive biological analysis method for miRNA-21 by preparing Au@Ag@4-MBA@5′-NH2-ssDNA probes and Ag/TiO2@3′-NH2-ssDNA substrates composed of sandwich structures [72]. SERS-based ELISA stands out as a molecular detection method with superior sensitivity and accuracy compared with conventional ELISA; therefore, it can serve various biological research and diagnostic purposes [73]. Experimental results demonstrated a low detection limit of 0.75 fM and a wide dynamic range of 1.0 fM to 1.0 nM for SERS-based sandwich biological assays of miRNA-21. Consequently, utilizing SERS for detecting biomarkers such as miRNA can significantly reduce measurement time and enable accurate detection (Figure 4).

Magnetic Core–Metal Shell (Fe3O4@metal)

The use of Fe3O4@metal core-shell NPs has been proposed to circumvent the cumbersome separation process of nonmagnetic metals in SERS. The magnetic properties of such particles enable easy separation in solution, without the need for centrifugation; this significantly enhances efficiency and convenience relative to traditional methods relying on density differences [74,75]. This innovative approach is expected to contribute to enhancements in the reliability and efficiency of SERS analysis.
The advantage of such core–shell structures lies in their ability to possess magnetism while combining the characteristics of SERS materials such as Ag and Au; this ensures excellent SERS performance [74,75,76]. Consequently, these NPs have considerable potential to be utilized in SERS analysis.
Fe3O4@metal NPs are frequently employed for miRNA detection. Pang et al. developed a system that utilizes Fe3O4@Ag to sensitively and selectively detect miRNA let-7b, a biomarker for cancer cells, with an LOD of 0.3 fM (Figure 5a) [77]. Jiang et al. reported the sensitive detection of exosomal miRNA, a challenging early diagnostic biomarker for cancer, using Fe3O4@ TiO2-based SERS; they achieved an LOD of 0.21 fM, which enabled accurate quantification (Figure 5b) [77].

3.2. 2D Materials

As SERS substrates, inorganic materials are classified into two contrasting categories: semiconductors and lamellar materials. Semiconductors such as zinc oxide (ZnO), titanium oxide (TiO2), and tungsten oxide (WO3) are favorable as SERS substrates due to their stability, cost-effectiveness, and strong optical performance [17,28,79,80]. By contrast, lamellar substrates, especially 2D materials such as MXene and graphene, can be effective as SERS substrates due to their versatility, tunability, and electrochemical and optical properties [81]. Their intrinsic properties make them ideal for next-generation biosensors, including SERS-based platforms [81,82]. Semiconductors usually accent the substrate’s electron structures and increase the likelihood of charge transfer between the substrate and the detection molecules. Instead, lamellar materials rely on the correlation between their distinct physicochemical properties and the quasi-2D morphology of the substrates [28]. Unlike plasmonic materials or noble metals, which harness EM, these materials predominantly leverage CM for SERS amplification [36]. The subsequent subsections discuss the composition of MXene and graphene in detail, as well as their recent applications.

3.2.1. MXene

MXenes are 2D materials comprising transition metal carbides or nitrides with several atomic layers [81]. MXenes used as lamellar substrates are fabricated by selectively extracting the “A” layers from the MAX phase template through hydrofluoric acid (HF) etching or non-HF etching; this results in the delamination of layers, creating thin 2D sheets [81,82,83]. The MAX phases are layered compounds comprising transition metals (denoted as “M”), Group 13 and 14 elements on the periodic table (denoted as “A”), and carbon and/or nitrogen (denoted as “X”) [81,83,84]. Accordingly, after the removal of “A,” an MXene is expressed by the formula Mn+1XnTx, where “n” corresponds to the number of X layers—which varies from 1 to 3—while “Tx” denotes the surface functionality group (e.g., –OH, =O, –F, and occasionally –Cl) [81,82,83,84,85]. MXenes offer several advantages in sensor fabrication, including distinctive optical properties that are ascribed to their extensive adsorption band in nanosheet form and their substantial energy levels [85].
To further improve the structural and optical properties of MXenes for biosensing applications, studies have attempted to combine them with other nanomaterials such as metallic NPs, metal nano-oxides, enzymes, and antibodies [85]. For instance, a mechanical engineering group developed an ultrasensitive miRNA-182 detection platform for cancer diagnosis (Figure 6). A high detection sensitivity was achieved by choosing the average intensities of three Raman peaks, corresponding to MXene (611 cm−1) and MoS2 (382 and 402 cm−1), as a benchmark. The use of an MXene/MoS2@AuNPs (MMA) configuration ensured a synergistic SERS strategy that yielded highly repeatable and specific selectivity outputs by leveraging I1362/Irf values to remove external interferences and fluctuations. Additionally, numerous hotspots were obtained using this MMA-based SERS system, which formed a significant number of “hot spots” by precisely controlling the synthesis to maintain a particle gap of 2.2 nm between the AuNPs and the surface of the MXene/MoS2, as well as anchoring the AuNPs homogeneously and solidly. A high linearity was recorded (R2 = 0.9995) for the calibration of the three peaks, with an LOD of 6.61 aM and a detection range of 10 aM to 1 nM for miRNA-182 [86]. A detailed description of the MXene materials used in SERS is presented (Table 1).

3.2.2. Graphene

Graphene-based nanomaterials, characterized by semimetals with a zero bandgap, commonly include graphene, GO, and reduced GO [82,87]. Graphene, with a thickness of a single atomic layer and densely packed honeycomb lattice structures, is a 2D carbon lamellar material [80,88]. The single atomic layer of graphene is prepared via the hybridization of carbon atoms with an sp2 electron orbital, which yields honeycomb lattice structures. In the fabrication of biosensor platforms, graphene is preferred due to its wide surface area, excellent electron transport capability, high mechanical strength, and pliability [87]. In terms of SERS-based detection, graphene can enhance the signal outputs via CM through the first-layer effect of graphene-enhanced Raman scattering [81,89]. Thus, SERS-based graphene biosensors represent an ideal detection platform, especially for tracing biomolecules such as miRNA, due to their quantitative and repeatable recognition capability [88,90].
Although inorganic materials generally offer lower SERS efficiency compared with noble metal materials, integrating them with noble metal materials could alleviate this weakness, thereby enabling more accurate detection. In this regard, Song et al. employed nanodendritic Au/graphene to develop a tri-modal biosensing platform for miRNA-375 detection with highly wettable surfaces. Three types of detection techniques were utilized: SERS, electrochemical techniques, and fluorescence optical techniques. With focusing on the SERS-based graphene biosensors, the integration of graphene enhanced not only the SERS and electrochemical signals, but also the fluorescence outputs, due to the varied absorption behavior of the single and double nucleic acid strands [91].
Despite the benefits of integrating 2D materials with noble metals, this strategy has certain limitations. Majorly, the volatile adhesion between the two types of materials could compromise selectivity. Additionally, the complicated system design limits the scalability of the manufacturing process. Liu et al. recently designed a mechanically stable, flexible, and sensitive Ti3C2Tx MXene@graphene oxide/Au nanocluster (MG/AuNCs) fiber substrate via wet spinning followed by in situ reduction processes (Figure 7). The fabricated MG fiber substrate exhibited considerable flexibility (114 MPa) and enabled effective charge transfer, thus improving the CM effect for SERS-based sensors. Furthermore, the AuNCs grown on the substrate surface provided ultrasensitive hotspots for EM, in addition to enhancing the durability and performance of the system, especially in complex environments. This combination of 2D materials and noble metals provides insight into SERS enhancement strategies [92]. However, based on our search of the literature, there remains room for improvement in miRNA detection via MXene/graphene-based SERS detection platforms. In detail, there is still a gap in knowledge to be filled, especially in terms of studies conducted on MXene/graphene-based SERS detection focusing on miRNA as target biomarkers.
Table 1. SERS-based biosensor platforms for miRNA detection.
Table 1. SERS-based biosensor platforms for miRNA detection.
MaterialLaser WavelengthLaser PowerLODTargetReference
Au785 nm-0.046 pMmiRNA-21[47]
Au785 nm4.0 mW1.17 pM
2.18 pM		miRNA-21
miRNA-196 a-5		[93]
Au785 nm5 mW46.94 aMmiRNA196b[94]
Au633 nm-1 pMExosomal RNA[95]
Ag633 nm0.08 mW393 aM
176 aM
144 aM		miRNA-21
miRNA-486
miRNA-375		[54]
Ag633 nm-8.55 aMmiRNA-106a[96]
Core-shell785 nm499.95 mW0.75 fMmiRNA-21[72]
Core-shell785 nm-0.3 fMmiRNA lett-7b[78]
Core-shell785 nm10 mW0.21 fMmiRNA-10b[77]
MXene532 nm-6.61 aMmiRNA-182[86]

4. SERS-Based Biosensor Platforms for miRNA Detection

SERS technology is combined with various biosensors to complement the shortcomings of existing technologies and maximize their advantages. For this reason, many SERS-based biosensors have been developed, including LFA and ELISA. Applications to ELISA are covered in Section Gold Core–Silver Shell (Au@Ag). Below, we discuss in depth the advantages, principles, and recent applications of LFA technology for miRNA detection [36,97,98,99].
Integration with SERS can refine the detection limits of conventional LFA, while also facilitating the quantification of target biomarkers. Principally, SERS-based LFA maintains the conventional LFA concept, only replacing colloidal AuNPs with SERS nanotags. On the test strip in LFA, the capillary action causes the sample solutions to progress chromatically from the sample pad toward the absorbent pad. During this process, a complex comprising a SERS immunoprobe bonded to the target biomarkers in the biological sample is captured by the immobilized antibody on the T-line, and the remaining unbounded complexes progress further before being captured on the C-line. Ultimately, the targets are observable through color changes in the test zone and the quantification of the signal outputs in the SERS spectrum from the T-line. Thus, the SERS-based LFA technique further enhances the sensing system’s advantages, especially in clinical diagnostics [97,98,99,100,101].
Considering the challenges associated with early disease screening, the accurate and highly sensitive quantification of miRNAs in bodily fluids is imperative. To this end, Cao et al. fabricated a SERS-based LFA for the tsimultaneous detection of lung cancer–linked miRNAs, specifically miRNA-196a-5p and miRNA-31-5p, with a catalytic hairpin assembly (CHA) for signal amplification. In this system, biotinylated hairpin DNA and Monoclonal IgG modified to Au-AgNSs@4-ATP and Au-AgNSs@DTNB are utilized as the SERS tags, which are complementary to the targeted miRNA. Based on the results, LODs as low as 1.171 nM and 2.251 nM in phosphate buffer and 1.681 nM and 2.603 nM in human serum were achieved for miRNA-196a-5p and miRNA-31-5p, respectively. Additionally, faster detection was achieved through the entire process. With reference to conventional miRNA detection using real-time PCR, this SERS-based LFA biosensor achieved comparable results. Hence, it represents a promising tool for miRNA research, especially in the biomedical field [102].
Mao et al. utilized SERS-based LFA for the detection of miRNAs linked with non-small cell lung cancer (NSCLC). Specifically, miRNA-21 and miRNA-196a-5p were detected with a CHA for signal amplification. Two SERS tags were fabricated by functionalizing Raman molecules such as 4-MBA or DTNB on the surface of gold nanocages (GNCs) with two hairpin DNA sequences. Targeted miRNAs were detected simultaneously in under 30 min by classifying urine samples from patients with NSCLC and healthy subjects. LODs as low as 2.08 pM and 3.31 pM were achieved in phosphate buffer and human urine, respectively, for miRNA-21; for miRNA-196a-5p, the LODs were 1.77 pM and 2.18 pM in phosphate buffer and human urine, respectively (Figure 8a) [93].
While the early diagnosis of diseases is important, obtaining quantified signals with minimal background noise is critical for avoiding false negatives. In this regard, another research group employed the SERS-based LFA approach with CHA-based signal amplification for detecting miRNAs associated with laryngeal squamous cell carcinoma (LSCC). The target biomarkers were miRNA-106b and miRNA-196b. The SERS-LFA system was assembled with two Raman molecules—4-MBA and DTNB—labeled on the surface of palladium core–gold shell nanorods, together with two biotinylated hairpin DNAs complementary to the targets. The biosensor achieved swift quantification of the target miRNA in serums from healthy subjects and patients with LSCC, with consistent outputs comparable to those from qRT-PCR. The measured LODs for miRNA-106b and miRNA-196b were as low as 23.17 aM and 46.94 aM, respectively, in phosphate buffer; this confirms the SERS-based LFA system is reliable, selective, and highly sensitive (Figure 8b) [96].

5. SERS-Based Nucleic Acid Amplification

Nucleic acid amplification techniques, such as PCR, amplify small amounts of nucleic acids using polymerase enzymes to enable the detection of minute quantities of nucleic acids. PCR, which was widely used for diagnosis during the COVID-19 pandemic, is a representative method for nucleic acid amplification, known for its high sensitivity and specificity. Hence, it is the gold standard technique for nucleic acid biomarker detection. Nevertheless, PCR has several limitations that must be addressed. The main drawback is the requirement for multiple thermal cycles, which results in a lengthy process and necessitates thermal cyclers and skilled experts for operation. To circumvent this, isothermal nucleic acid amplification methods, such as hybridization chain reaction (HCR) and rolling circle amplification (RCA), have been developed; by maintaining a constant temperature, these techniques obviate the need for thermal cycling and skilled personnel. Combining nucleic acid amplification with SERS can enable more sensitive biomarker detection compared with using only conventional SERS methods. This is possible because amplifying the target biomarker through nucleic acid amplification provides stronger signals.
The HCR is triggered by the addition of initiators to complementary DNA hairpins, labeled H1 and H2 [103]. This leads to the unfolding of the hairpin structures for complementary binding between DNA strands, which subsequently triggers the binding of other hairpins in a repetitive manner, resulting in amplification. HCR offers the advantage of being enzyme-free and isothermal [104]. Chen Q et al. achieved sensitive and rapid detection using a combination of Au@AgNPs and SERS. They utilized SERS-based HCR to sensitively detect miRNA-210, which reduces the activity of γ-globin for the treatment of β-thalassemia, achieving an LOD of 1.17 pM [105]. Zhang J et al. used CRISPR/Cas13 and SERS-based HCR to sensitively detect miRNA106a, a biomarker for gastric cancer, achieving an LOD of 8.55 aM. Furthermore, the detection was exceptionally rapid, requiring only 60 (Figure 9a) [96].
RCA, an isothermal amplification method distinct from HCR, amplifies the sequences of circular nucleic acids such as DNA or RNA through repetitive cycles [106]. Primers are first attached to the circular nucleic acid template, followed by the replication of single-stranded DNA with repetitive sequences complementary to the template [107]. RCA can amplify the target signal without temperature fluctuations and at room temperature, while offering high sensitivity and specificity. Hence, it is suitable for utilization in lab-on-a-chip platforms. Qian J et al. combined a lab-on-a-chip system with the SERS-based RCA method for the detection of miRNA-21 and miRNA-155, biomarkers for idiopathic pulmonary fibrosis (IPF). Diagnostics for IPF presently rely on invasive methods to assess tissue damage. However, the SERS-based RCA method on a lab-on-a-chip platform enabled the noninvasive detection of miRNA-21 and miRNA-155, with LODs of 0.29 fM and 0.37 fM, respectively [108]. Zhao Y et al. developed a lab-on-a-chip system capable of measuring SERS following the RCA amplification of exosomal miRNA, specifically miRNA-21, which is linked with MCF-7 breast cancer cells. The system achieved the sensitive detection of miRNA-21, with an LOD of 1 pM (Figure 9b) [95].

6. Conclusions

miRNAs have gained prominence as excellent biomarkers for the early diagnosis of various types of diseases. However, conventional analytical methods, such as northern blots, RT-qPCR, and NGS are complex, time-consuming, and costly. SERS has emerged as an alternative method for miRNA measurement that can overcome these limitations while maintaining reliability. In this review, we discussed the principles of SERS, exemplary SERS substrates such as Au and Ag, and materials such as graphene and MXene. We also explored their features and applications in various analysis methods, including combinations of SERS with LFA, ELISA, and PCR.
Au and Ag have been widely utilized due to their excellent properties as SERS substrates. However, they are hindered by certain limitations, which have been addressed by developing composites such as Au@Ag or by utilizing magnetic properties to create core–shell nanostructures such as Fe3O4@metal. In addition, combinations of SERS with existing detection methods have also been explored. LFA and ELISA are immunoassay methods based on antigen–antibody interactions, and SERS can enhance their detection sensitivity. However, despite these advancements, certain limitations of SERS have been identified as well. For instance, the SERS performance of portable Raman spectrometers is compromised, which renders them unable to measure SERS signals sensitively and thus limits their utility in on-site diagnostics. Consequently, the development of high-performance portable Raman spectrometers could enable on-site diagnostics, particularly in underserved regions such as developing countries with limited medical facilities. Such technological progress is anticipated to contribute significantly to advancements in global healthcare. Besides this, the construction of increasingly sophisticated production systems is required to improve the reproducibility, scalability, and precise nanometer control of nanostructures generated in the manufacturing process before the SERS platform is implemented industrially. Finally, the use of machine learning to increase reproducibility and practicality will enable measurements with fewer errors as machines perform measurements, so it is worth noting the need for machine learning and the development of production systems.

Author Contributions

J.-H.C. and S.B.S. organized the structure of the manuscript; S.B.S., I.H., M.Y.C. and Y.L. wrote the whole manuscript; J.-H.C., S.B.S., I.H., M.Y.C. and Y.L. revised the manuscript. All authors collaboratively wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by research funds for newly appointed professors of Jeonbuk National University in 2021, the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2023-00236157), and by grants from the Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. The main mechanisms behind SERS. Schematic of electromagnetic interaction in SERS. The arrows indicate that the nanoparticles are undergoing plasmon resonance due to the wavelength.
Figure 1. The main mechanisms behind SERS. Schematic of electromagnetic interaction in SERS. The arrows indicate that the nanoparticles are undergoing plasmon resonance due to the wavelength.
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Figure 2. (a) Processes of the proposed biosensor utilizing an Au array and DTNB molecules. The complementary binding of H1 with the target enables sensitive detection of the target miRNA. Reproduced with permission from [50]. (b) Schematic of CRISPR-Cas12a-based nucleic acid amplification-free biosensor using a SERS-assisted detection system. The GO/TANF array is designed to generate hotspots effectively, thereby enhancing the Raman signal. Reproduced with permission from [48].
Figure 2. (a) Processes of the proposed biosensor utilizing an Au array and DTNB molecules. The complementary binding of H1 with the target enables sensitive detection of the target miRNA. Reproduced with permission from [50]. (b) Schematic of CRISPR-Cas12a-based nucleic acid amplification-free biosensor using a SERS-assisted detection system. The GO/TANF array is designed to generate hotspots effectively, thereby enhancing the Raman signal. Reproduced with permission from [48].
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Figure 3. (a) Schematic of charge transfer effect on SERS in a semiconductor–molecule–metal system sandwich-constructed with AgNPs, 4-MBA molecules, and atomic-level TiO2. Reproduced with permission from [53]. (b) Schematic illustrating the preparation and application of a molecular beacon functionalized-SERS sensor for simultaneously measuring multiple miRNAs with AgNR arrayed substrate. Reproduced with permission from [54].
Figure 3. (a) Schematic of charge transfer effect on SERS in a semiconductor–molecule–metal system sandwich-constructed with AgNPs, 4-MBA molecules, and atomic-level TiO2. Reproduced with permission from [53]. (b) Schematic illustrating the preparation and application of a molecular beacon functionalized-SERS sensor for simultaneously measuring multiple miRNAs with AgNR arrayed substrate. Reproduced with permission from [54].
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Figure 4. Schematic of the SERS-ELISA functionalizing steps. The SERS substrate, composed of AgNWs arranged in a periodic pattern, is coated with an ssDNA that specifically recognizes miRNA-21. Reproduced with permission from [72].
Figure 4. Schematic of the SERS-ELISA functionalizing steps. The SERS substrate, composed of AgNWs arranged in a periodic pattern, is coated with an ssDNA that specifically recognizes miRNA-21. Reproduced with permission from [72].
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Figure 5. (a) Schematic illustrating the detection of miRNA using Fe3O4@Ag and the subsequent amplification of Raman signals [78]. (b) Schematic elucidating the enhancement of SERS signals for miRNA within exosomes utilizing Fe3O4@TiO2. Reproduced with permission from [77].
Figure 5. (a) Schematic illustrating the detection of miRNA using Fe3O4@Ag and the subsequent amplification of Raman signals [78]. (b) Schematic elucidating the enhancement of SERS signals for miRNA within exosomes utilizing Fe3O4@TiO2. Reproduced with permission from [77].
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Figure 6. MXene as an inorganic material in SERS biosensors for miRNA detection. Schematic illustration of MMA-based SERS system for the detection of miRNA-182. MXene is utilized as a SERS substrate attached to MoS2 and AuNPs to generate hotspots for signal enhancement. Reproduced with permission from [86].
Figure 6. MXene as an inorganic material in SERS biosensors for miRNA detection. Schematic illustration of MMA-based SERS system for the detection of miRNA-182. MXene is utilized as a SERS substrate attached to MoS2 and AuNPs to generate hotspots for signal enhancement. Reproduced with permission from [86].
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Figure 7. Graphene as an inorganic material in SERS detection platform. Schematic illustration of mechanically sensitive, flexible, and durable Ti3C2Tx MG/AuNC fiber substrate. Graphene is integrated with MXene and a noble metal (Au) to boost the CM and EM for the sensing system. Reproduced with permission from [92].
Figure 7. Graphene as an inorganic material in SERS detection platform. Schematic illustration of mechanically sensitive, flexible, and durable Ti3C2Tx MG/AuNC fiber substrate. Graphene is integrated with MXene and a noble metal (Au) to boost the CM and EM for the sensing system. Reproduced with permission from [92].
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Figure 8. SERS-based LFA biosensor platform for miRNA detection. (a) Schematic of SERS-based LFA platform paired with CHA for signal amplification for two specific NSCLC-related miRNAs with GNCs as SERS tags. Reproduced with permission from [93]. (b) Schematic of SERS-based LFA system for dual LSCC-associated miRNA detection via Pd core–Au shell NRs assisted with CHA for signal amplification. Reproduced with permission from [94].
Figure 8. SERS-based LFA biosensor platform for miRNA detection. (a) Schematic of SERS-based LFA platform paired with CHA for signal amplification for two specific NSCLC-related miRNAs with GNCs as SERS tags. Reproduced with permission from [93]. (b) Schematic of SERS-based LFA system for dual LSCC-associated miRNA detection via Pd core–Au shell NRs assisted with CHA for signal amplification. Reproduced with permission from [94].
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Figure 9. SERS-based nucleic acid amplification methods. (a) Schematic illustration of SERS-based HCR to detect miRNA106a. The target miRNA binds to crRNA, activating CRIPR/Cas13, which cleaves recognition probe from the reconstituted trigger. Reproduced with permission from [96]. (b) Schematic illustration of the SERS-based RCA lab-on-a-chip platform, which captures and lyses exosomes in the magnetic enrichment zone to release abnormal miRNA, subsequently capturing them in the target capture zone and confirming the SERS signal. Reproduced with permission from [95].
Figure 9. SERS-based nucleic acid amplification methods. (a) Schematic illustration of SERS-based HCR to detect miRNA106a. The target miRNA binds to crRNA, activating CRIPR/Cas13, which cleaves recognition probe from the reconstituted trigger. Reproduced with permission from [96]. (b) Schematic illustration of the SERS-based RCA lab-on-a-chip platform, which captures and lyses exosomes in the magnetic enrichment zone to release abnormal miRNA, subsequently capturing them in the target capture zone and confirming the SERS signal. Reproduced with permission from [95].
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Sim, S.B.; Haizan, I.; Choi, M.Y.; Lee, Y.; Choi, J.-H. Recent Strategies for MicroRNA Detection: A Comprehensive Review of SERS-Based Nanobiosensors. Chemosensors 2024, 12, 154. https://doi.org/10.3390/chemosensors12080154

AMA Style

Sim SB, Haizan I, Choi MY, Lee Y, Choi J-H. Recent Strategies for MicroRNA Detection: A Comprehensive Review of SERS-Based Nanobiosensors. Chemosensors. 2024; 12(8):154. https://doi.org/10.3390/chemosensors12080154

Chicago/Turabian Style

Sim, Sang Baek, Izzati Haizan, Min Yu Choi, Yubeen Lee, and Jin-Ha Choi. 2024. "Recent Strategies for MicroRNA Detection: A Comprehensive Review of SERS-Based Nanobiosensors" Chemosensors 12, no. 8: 154. https://doi.org/10.3390/chemosensors12080154

APA Style

Sim, S. B., Haizan, I., Choi, M. Y., Lee, Y., & Choi, J. -H. (2024). Recent Strategies for MicroRNA Detection: A Comprehensive Review of SERS-Based Nanobiosensors. Chemosensors, 12(8), 154. https://doi.org/10.3390/chemosensors12080154

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