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Molybdenum Disulfide as Tunable Electrochemical and Optical Biosensing Platforms for Cancer Biomarkers Detection: A Review

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27 July 2023

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28 July 2023

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Abstract
Cancer is a common illness with a high mortality. Compared to traditional technologies, biomarkers detection, with low cost and simple operation, has higher sensitivity and faster speed in early screening and prognosis of cancer. Therefore, extensive research has been focused on the development of biosensors and the construction of sensing interfaces. Molybdenum disulfide (MoS2) is a promising two-dimensional (2D) nanomaterial, whose unique adjustable bandgap shows excellent electronic and optical properties in the construction of biosensor interfaces. It not only has the advantages of high catalytic activity and low manufacturing costs, but also can further expand the application of hybrid structures by different functionalization, and is widely used in various biosensors fields. Herein, the application of electrochemical and optical sensing platforms based on MoS2 in the detection of cancer biomarkers was comprehensively reviewed. Firstly, the structure and preparation method of MoS2 were introduced, and its applicable characteristics in the field of biosensors were explored. Secondly, we comprehensively reviewed the recent construction and application of sensing platform based on MoS2 in the field of cancer biomarkers detection in both electrochemical and optical aspects. The prime characteristics and application performances of MoS2 and its composites were emphasized. Additionally, we also involved some other types of biosensors based on MoS2. Finally, we summarized the challenges and development prospects of MoS2 in the application of cancer biomarkers detection, and provided some insights for the application potential of this kind of emerging nano-materials in a broader field.
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Subject: Biology and Life Sciences  -   Biochemistry and Molecular Biology

1. Introduction

Cancer is the world's largest cause of death and the second most common disease [1]. At present, more than 200 types of cancers have been found. In general, imaging technologies such as ultrasound, positron emission tomography (PET), magnetic resonance imaging (MRI), or computed tomography (CT) are used for early screening, and then confirmed by tissue biopsy and histology, so that patients can be treated in a timely manner, which can dramatically reduce cancer mortality [2,3]. However, traditional cancer detection methods are often invasive, expensive, complex, and time-consuming. Rapid diagnosis and early prevention are crucial for clinical treatment and management of cancer [4].Cancer biomarkers, as important components of detection, prognosis, and providing etiological analysis of cancer, are abnormal quantities of biological molecules generated by the body's response to the disease or directly by the cancer tumor itself, including DNA, RNA, genes, proteins, enzymes, peptides, exosomes, and metabolomics [5]. They typically exist in blood, urine, tears, oral fluids, and other tissues [6]. Cancer biomarker detection has accelerated the process of cancer diagnosis, and can obtain higher sensitivity and faster cancer screening. Enzyme linked immunosorbent assay (ELISA) [7], polymerase chain reaction (PCR) [8], clustered regularly interspaced short palindromic repeats Cas9 (CRISPR-Cas9) [9], loop-mediated isothermal amplification (LAMP), time-resolved fluorescence spectroscopy (TR-FS), radioimmunoassay (RIA) and electrophoresis [10] have been used for the detection of cancer biomarkers [11].
In recent years, compared with traditional technologies, biosensors have potential advantages such as high sensitivity and selectivity, high accuracy, low cost, fast detection, high stability, availability, and ease of operation. They play an important role in diagnosing and quantitatively analyzing biomarker concentrations, and are widely used in various fields such as healthcare, food inspection, and environmental testing [12]. Biosensors use various biomolecules as biometric recognition components, which are fixed on the sensor surface and converted into measurable electronic or optical signals through biological response with the detection target substance for cancer biomarker detection [13]. Biosensors can be divided into electrochemical, optical, mass dependent, and radiation sensitive biosensing platforms based on different transduction principles [14,15]. Developing efficient and practical biosensors usually requires consideration of the following aspects: (1) synthesis/manufacture/assembly of suitable sensing materials; (2) select appropriate recognition/capture molecules; (3) integration of sensor surfaces with biomolecules [16,17]. With the development of nanotechnology in medicine and biotechnology, more and more researchers are combining different types of nanomaterials with optical, electrical, mechanical, and magnetic sensors to design nanosensors for the detection of cancer biomarkers [18]. Nanobiosensors are generally composed of nanomaterials and a sensor based on biometric recognition elements [19]. They can be combined according to the interaction of affinity bond, covalent bond, cross-linking, capture and physical adsorption [20].
Among various nanomaterials, 2D layered nanomaterials have attracted widespread research interest due to their quantum confinement, high absorption coefficient, high specific surface area, and tunable bandgap characteristics [21]. Among them, Graphene has excellent physical properties, chemical adjustability and application potential, and its synthesis, properties and applications are widely concerned [22]. The impressive performance of Graphene in various fields has aroused a strong interest in the exploration of a wider range of 2D layered nanomaterials "beyond graphene" [23]. Transition metal dichalcogenides (TMDs), as a new class of stable inorganic graphene analogues, have been further studied. Among them, MoS2 is regarded as the representative of TMDs. Its single molecular layer is composed of the atomic layer of transition metal Mo sandwiched between two sulfur elements S [24]. Mo atoms and S atoms are closely connected by forming strong covalent bond through coordination, and the interlayer is connected by weak van der Waals force. This weak connection mode between layers provides conditions for MoS2 stripping to form a single-layer 2D planar structure [25], showing unique electronic, optical, mechanical and chemical properties [26,27,28]. Most importantly, due to the confinement of electrons/holes in ultra-thin planar structures, MoS2 is highly sensitive to changes in the microenvironment [29], thus exhibiting advantages in the construction of biosensing interfaces [30,31].
A large number of literatures have reported that kinds of biosensing platforms based on MoS2 are used to detect various biomarkers. Considering the needs of cancer biomarker detection in terms of high sensitivity, high reproducibility, easy processing, low cost and miniaturization. In this review, we will focus on the excellent characteristics and application performance of MoS2 and its hybrid structures. We will comprehensively review and summarize the recent sensor work based on MoS2 in the electrochemical and optical aspects for the detection of cancer biomarkers. Firstly, the preparation method of MoS2 and the excellent applicable characteristics in the field of biosensors are explored, and the detection of cancer biomarkers by electrochemical sensing and optical sensing based on MoS2 are introduced in detail respectively. Finally, we summarize the challenges and prospects of MoS2 in terms of synthesis, functionalization of composite groups, and applications, and provide some insights into the enormous potential of these emerging 2D nanomaterials in the field of cancer biomarker detection.

2. Synthesis and characteristics of molybdenum disulfide

MoS2 belongs to hexagonal lattice structure, as shown in Figure 1a. Its three common crystal structures are 1T, 2H and 3R, and their corresponding point groups are D6d, D6h and C3v [32]. In addition, an additional hypothetical 2T structure of MoS2 has been studied and reported [33]. Accordingly, 1, 2 and 3 represent the number of layers, T represents the triagonal configuration, H represents the hexagonal configuration, and R represents the rhombohedral configuration. The MoS2 layers in the 2H, 3R, 1T, and additional 2T crystal structures are arranged in anti parallel AB, parallel ABC, parallel AA, and anti parallel AA' stacking sequences, respectively [34]. The properties of MoS2 may show different characteristics according to the change of crystal structure [35]. Among these crystal structures, 2H-MoS2 exhibits thermal stability and exhibits semiconductor characteristics, making it the most widely used in practical applications. While 1T-MoS2 shows paramagnetism and metallicity [36], it shows metastability and is easy to convert into 2H-MoS2, which facilitates the photoelectric application of MoS2 [37]. In addition, the number of layers can also alter the electrical and optical properties of MoS2 nanosheets. For example, reducing the thickness of MoS2 nanosheets can improve conductivity and accelerate electron transfer rate [38]. The application of MoS2 in electronic devices is inseparable from its electronic band structure and electronic properties dependent on the density of states. Kuc et al. calculated the electronic band structure of MoS2, and obtained the electronic band structure diagram of MoS2 with different thicknesses (Figure 1b). The indirect band gap of blocky MoS2 is 1.2 eV. During the change from blocky structure to layered structure, the band gap thickness gradually increases (1.2 eV-1.9 eV) and transforms from indirect to direct band gap (1.9 eV), showing good absorption and photoluminescence characteristics [39,40]. Compared with graphene with 0 eV band gap, this adjustable band gap improves the application of MoS2 materials in the field of optoelectronics [41]. The key reason for the widespread application of MoS2 in optoelectronics is that it exhibits tunable band gap characteristics as it changes in size and structure. Different band gaps bring adjustable optical responsiveness, specific detection rate, and response time, thus having a wide range of applications [42].
By controlling the synthesis conditions of MoS2, various nanostructures can be synthesized. In addition to the most widely used 2D MoS2 nanosheets [43], they also include structures such as 0D quantum dots (QD) [44], 1D (nanotubes) [45], and 3D (nanoflowers) [46]. Various structures exhibit different characteristics, such as the direct band gap of nanosheets, photoluminescence of quantum dots, and the high surface area and volume ratio of nanoflowers, which make MoS2 exhibit unique and excellent performance in different application scenarios [47]. The synthesis methods of MoS2 can be roughly divided into two categories: top-down and bottom-up (Figure 2). The top-down methods mainly includes mechanical exfoliation, liquid-phase exfoliation, and chemical methods. The bottom-up methods mainly includes chemical vapor deposition (CVD) and solvothermal or hydrothermal methods [48].

2.1. Top-down methods

Mechanical exfoliation: As the MoS2 layers are connected by the weak van der Waals force, the layered MoS2 can be easily peeled off by friction of the bulk substrate MoS2 with tape. The peeled tape is pressed into the appropriate substrate, and the synthetic process of MoS2 mechanical exfoliation is completed by using the van der Waals force formed between MoS2 and the substrate. Silicon dioxide (SiO2) is currently the most widely used substrate material [50]. The mechanical exfoliation is limited by its low yield and therefore cannot be used for large-scale production. However, this method can produce layered MoS2 with ideal purity and large transverse size, and is often used as a laboratory preparation method for studying the properties of MoS2 materials [51].
Liquid-phase exfoliation: In order to overcome the low yield and difficulty in large-scale production of mechanical exfoliation, the process of stripping MoS2 in solution is called liquid-phase exfoliation. Specifically, the bulk MoS2 is dissolved in a suitable solution and separated from the layered MoS2 by methods, such as bubbling, ultrasonic dispersion, grinding, and shearing [52,53,54,55]. Among them, adding surfactants [56] or bubbling bubbles [57] in the solution can help improve the stability of MoS2, effectively maintain the layered structure of MoS2 after peeling, and prevent it from recombining with the bulk MoS2. Overall, liquid-phase exfoliation is simpler and more cost-effective than mechanical exfoliation, making it stand out in industrial applications [58].
Chemical methods: Chemical methods mainly rely on metal ions entering the interlayer of bulk MoS2 to achieve the detachment of MoS2 [58]. In the chemical stripping process, the most widely used metal ion reported is Li+. However, the intercalation of Li+ will simultaneously lead to the transfer of MoS2 from the 2H phase exhibiting semiconductor properties to the 1T phase exhibiting metal properties, which limits the application scenarios of the generated MoS2. Further research has shown that annealing at 300 ℃ can restore MoS2 formed by Li+ intercalation to the 2T phase [60]. Electrochemical methods have also emerged in the MoS2 stripping process, typically using block MoS2 as the cathode to achieve stripping. However, the large size and area of MoS2 produced by electrochemical stripping methods are limited in their application in the biological field, thus requiring more exploration [61].

2.2. Bottom-up methods

CVD: CVD is a typical nanomaterial growth technique that can be used to prepare high-quality MoS2 with scalable size, controllable thickness, and excellent electronic properties [61]. CVD uses precursor gas molecules to adsorb on the substrate surface and generate thermal chemical decomposition reaction, thus forming high-quality layered MoS2. At present, Mo precursors commonly used in CVD mainly include Mo and Molybdenum trioxide, while S precursors mainly use hydrogen sulfide gas or vaporized S [63,64]. On this basis, we further studied the CVD process of MoS2 using Molybdenum(V) chloride as a precursor. The characterization results verified that this precursor can produce a larger area of high-quality single-layer MoS2 films, but more precursors that can be used for CVD still need to be further explored [65]. CVD can not only produce MoS2 with high film quality, but also easily functionalize MoS2 by introducing other precursors during the preparation process. The entire process is very simple and convenient, and is commonly used for studying the properties of MoS2 materials and constructing biosensors [66].
Solvothermal or hydrothermal methods: Solvothermal or hydrothermal methods are a simple, scalable, and easily controllable method for preparing MoS2. The solvothermal method commonly uses solid precursors, while the hydrothermal method commonly uses liquid precursors [66]. Generally, under high temperature conditions, the molybdate that provide Mo source and the sulfides that provide S source are reacted in a polytetrafluoroethylene high-pressure reactor, and MoS2 is synthesized through the generated steam pressure. In most cases, annealing treatment is required to improve its crystal quality and purity [68]. This method can effectively preserve the 2H phase of MoS2 and achieve control the size parameters of MoS2 to a certain degree. The harmless preparation process further preserves the biocompatibility of MoS2, making it easier to obtain smaller microcrystals with high catalytic activity compared to CVD. It has great potential in constructing electrochemical and fluorescent biosensors [69].
In addition to the above methods, there are also some methods for the preparation of MoS2, such as physical vapor deposition (PVD), sputtering, vapor solid growth, etc. Due to the different principles and processes of preparation methods, the generated MoS2 exhibits different characteristics and is applied in different scenarios accordingly. The large size of MoS2 prepared by mechanical exfoliation limits its biosensing application. Similarly, PVD exhibits harmful reverse defects compared to CVD during functionalization, which also affects its application range. Correspondingly, CVD and solution chemistry processes have been more widely promoted due to their adjustable preparation process and high-quality synthesis of MoS2. The construction of electrochemical/optical sensors using the electrical/optical properties of MoS2 has been extensively reported.

3. Electrochemical biosensors for cancer biomarkers detection based on MoS2

Electrochemical sensors are mainly composed of sensitive components, signal transduction components, and nano modified electrode structures. Electrochemical analysis technology is an important detection method in the field of biomedicine. Its basic principle is to analyze the changes in current or impedance signals generated by the interaction between the analyte and the electrode surface. It can monitor the charge movement between reaction interfaces and has significant advantages in fast response [70]. In recent years, sensitive electrochemical biosensors have been developed for the detection of cancer biomarkers [71]. MoS2 has been widely used in the field of electrochemical sensing of cancer biomarkers due to its excellent physical and chemical properties, excellent catalytic activity and low manufacturing costs. In this chapter, we will divide electrochemical biosensors into potentiometry, amperometry, impedimetry and photoelectrochemical (PEC) according to different signal transduction, and introduce the latest application progress of MoS2 in cancer biomarker detection.

3.1. Potentiometry

Potentiometric sensors obtain information about analytes by measuring the current when potential changes, mainly including chronoamperometry (CA), cyclic voltammetry (CV), differential pulse voltammetry (DPV) and square wave voltammetry (SWV), which are widely used electrochemical analysis methods. These methods fix the biometric elements (such as antibodies, enzymes and aptamers) on the electrode surface, and monitor the current changes triggered when the analyte combines with the biometric element when the potential between the working electrode and the reference electrode remains constant. Within the linear potential range, the peak current value monitored is directly related to the concentration of the target analyte in the solution, so as to realize the detection of the target.
The electronic properties of MoS2 are highly dependent on its phase structure. The ultra-thin MoS2 has good performance, but it is difficult to maintain stability in an independent state and is easy to aggregate [72]. In order to improve this problem, Ying et al. [73] used liquid-phase exfoliation and surface modification to synthesize 2H-MoS2 (Figure 3a), and used platinum nanowires (Pt NWs) arrays as nanopillars, which were added to the ultra-thin 2D MoS2 interlayer to form Pt NWs arrays@MoS2 nano hybrid, which improved the specific surface area and porosity, and could be used as "electronic wires" to catalyze electron transfer at the interface, avoiding folding by creating new dimensions. Thus, stability and current signal enhancement are achieved.
Two main reasons that limit the practical application of MoS2 in electrochemical sensing are that the strong van der Waals force effect between layers leads to aggregation and relatively low conductivity in layers [74]. In order to overcome these shortcomings, Su et al. [75] synthesized ionic liquid (IL) functionalized AuNPs/MoS2/rGO nanocomposites for sensitive detection of cancer specific target nucleolin (Figure 3b). The linear range of the unlabeled electrochemical sensor obtained is 0.5 nM-1.0 μM, and detection limit is 0.16 nM. Graphene has a large π electronic structure and edge, because of the synergistic effect, the combination of MoS2 and graphene can significantly improve the conductivity and large surface area of MoS2 [76]. In addition, the introduction of AuNPs into nanocomposites can not only fix the thioaptamer through the Au-S bond, which improves the affinity and specificity, but also enhance electron transfer and amplify the electrochemical signal.
Song et al. [77] modified rGO/MoS2@polyaniline nanosheets of 3D arrays on the surface of Au electrode and further incubated carcinoembryonic antigen (CEA) specific antibodies to achieve high sensitivity detection of CEA (Figure 3c). First, the sensor combines rGO with MoS2 to improve the stack phenomenon of MoS2, thus effectively enhancing the electron transfer efficiency of the electrode. Then, polyaniline was further embedded to introduce a large number of amino groups that can bind to CEA specific antibodies, and CEA was detected using CV in a wide linear range (0.001 ng/mL-80 ng/mL), with a limit of detection (LOD) of 0.3 pg/mL. Gui et al. [78] synthesized ce-MoS2/AgNR composites by using the van der Waals force and electrostatic interaction between chemically exfoliate MoS2 nanosheets (ce-MoS2) and Ag nanorods (AgNRs). Due to the synergistic effect, the conductivity of ce-MoS2/AgNR composites have increased by nearly twice. The unlabeled electrochemical immunosensor (EI) prepared can sensitively detect prostate specific antigen (PSA) in a wide linear range (0.1 ng/ml-1000 ng/ml) (Figure 3d), with a detection limit as low as 0.051 ng/ml, and have broad application potential in the clinical diagnosis of prostate cancer.

3.2. Amperometry

Amperometric sensors achieve quantitative detection of analytes by applying a constant voltage to the sensing platform to detect the current generated by the conversion of corresponding electroactive substances. Due to their convenience and high accuracy, they are widely used in the detection of cancer biomarkers. Due to the excellent catalytic activity of MoS2 for the reduction of H2O2, Ma et al. [79] used hydrothermal method to combine MoS2 nanoflowers (MoS2 NFs) with p-type metal semiconductor oxide cuprous oxide (MoS2@Cu2O) (Figure 4a), and at the same time, the introduction of AuNPs generated MoS2@Cu2O-Au complexes by Au-S bond as nanoprobes for signal amplification. The sandwich immunosensor constructed can detect the cancer marker alpha fetoprotein (AFP) of primary liver cancer in the wide linear range of 0.1 pg/mL to 50 ng/mL, demonstrating good application prospects. Ma et al. [80] have prepared a sandwich-type electrochemical immunosensor for the sensitive detection of CEA by coupling tri-metallic yolk-shell Au@AgPt nanocubes (Au@AgPt YNCs) loaded on amino-functionalized MoS2 NFs (MoS2 NFs/Au@AgPt YNCs) with secondary antibodies (Figure 4b). Due to the biphasic synergistic catalysis, the synthesized MoS2 NFs/Au@AgPt YNCs as a signal label effectively catalyzes the reduction of H2O2 to amplify the current signal, and realizes the high-precision detection of CEA in the range of 10 fg/mL-100 ng/mL, with the LOD as low as 3.09 fg/mL (S/N=3). These works provide ideas for the composite modification of MoS2 with different nano forms and further applications in biosensing platforms.

3.3. Impedimetry

Impedance sensors are an important type of electrochemical sensing that obtains information about analytes by measuring the conductance through interface reactions on the electrode surface. This type of sensor is very sensitive to the change of electrode, and is in an advantageous position in the detection of biomarkers. Therefore, it is also widely introduced into the construction of electrochemical sensing platform for the detection of cancer biomarkers. Jia et al. [81] prepared a novel nanohybrid of polyoxometalate-derived MoS2 nanosheets (pd-MoS2 NSs) by a hydrothermal method, which exhibited excellent electrochemical activity and abundant catalytic sites. Furthermore, pd-MoS2 NSs were vertically grown over β-FeOOH NRs (pd-MoS2@β-FeOOH) serving as complementary DNA platforms for fixing oncogenes and tumor suppressor miRNA-21, using electrochemical impedance spectroscopy (EIS) to detect miRNA-21, with a LOD as low as 0.11 fM. In addition, microfluidic electrochemical immunochips have been evaluated as a powerful detection platform because of its high sensitivity, low cost, portability and easy miniaturization. Sri et al. [82] synthesized MoS2 NFs by the same method, and electrophoretically deposited them on indium tin oxide (ITO) coated glass substrate. Due to the morphology of MoS2 NFs, antibodies can be effectively fixed on the electrode surface through physical adsorption. The biosensor can sensitively detect tumour necrosis factor-ɑ (TNF-ɑ) between 1-200 pg/ml, LOD as low as 0.202 pg/ml (Figure 4c). Hu et al. [83] first prepared MoS2 by liquid-phase exfoliation and formed a hybrid film with PDDA, designed a three-electrode system in the microfluidic chip, introduced MoS2/PDDA film modified with anti-AFP as the working electrode, Ag/AgCl as the reference electrode, and ITO as the counter electrode (Figure 4d). The linear range of AFP detected by EIS was 0.1 ng/mL to 10 ng/mL, the LOD is 0.033 ng/mL.

3.4. Photoelectrochemistry (PEC)

PEC utilizes photosensitive materials at the electrode interface as signal converters to analyze the electrical signals generated by analytes under light irradiation, combining the advantages of spectral analysis and electrochemical technology. MoS2 exhibits excellent characteristics of tunable bandgap in its transition from blocky structure to layered structure. The quantum confinement effect leads to good visible light absorption and photoelectric conversion efficiency of layered MoS2 as a direct bandgap semiconductor under visible light excitation, resulting in photocurrent generation. Therefore, it has been introduced into the application of photoelectrochemical sensing platforms. Hu et al. [84] utilized this mechanism to design a PEC sensing platform based on MoS2/Au/GaN for high sensitivity detection of AFP (Figure 4e). MoS2 can suppress the charge transfer of Au/GaN photoelectrodes, leading to a significant decrease in photocurrent. However, the presence of AFP can reduce the inhibitory effect on photocurrent, thereby utilizing the difference in photocurrent to detect AFP. AFP detection is achieved in a wide linear range of 1.0-150 ng/mL, with a LOD of 0.3 ng/mL. This method has good sensitivity and high selectivity for AFP detection. Wei et al. [85] synthesized a light responsive ZnS/C/MoS2 nanocomposite to construct a PEC immunosensor for detecting CEA, with a linear range of 2.0 pg/mL-10.0 ng/mL and the LOD of 1.30 pg/mL (S/N=3), showing good analytical characteristics (Figure 4f). In addition to the above sensing methods, other sensing methods based on MoS2 are listed in the Table 1 to detect various cancer biomarkers.

4. Optical biosensors for cancer biomarkers detection based on MoS2

Optical biosensors bring additional advantages in the fields of biotechnology, environmental research, disease diagnosis, and medical applications due to their high selectivity, fast, and sensitive measurement. The working principle and key performance indicators of optical biosensors largely depend on the optical transducers tightly integrated with biological sensing components [100]. Based on different biosensor elements, optical biosensors are divided into colorimetry, electrochemiluminescence (ECL), fluorescence, surface enhanced raman scattering (SERS), surface plasmon resonance (SPR) and other sensing methods. In combination with MoS2, the latest application progress in cancer biomarker detection is introduced respectively.

4.1. Colorimetry

MoS2, with its large surface area and exposed reaction sites, can be used as a nano enzyme to show the catalytic activity and excellent stability of peroxidase, and simulates natural enzymes to make the substrate color change. This feature is used to build a colorimetric sensor to detect cancer biomarkers [101,102]. Zhao et al. [103] introduced an aptamer to enhance the catalytic activity of MoS2 NSs on peroxidase substrates and designed a colorimetric sensor for intuitive detection of CEA, achieving sensitivity detection of CEA by recording absorbance successfully (Figure 5a). The sensor exhibits a linear response in the range of 50 to 1000 ng/mL, with a LOD of 50 ng/mL, demonstrating good specificity and practical application capabilities. Shao et al. [104] utilized the high catalytic activity of MoS2-AuNPs nanohybrids to reduce NaBH4 to 4-NP and make the yellow solution colorless, and constructed a colorimetric immunosensor for CEA detection (Figure 5b). The absorbance peak intensity of the colorimetric sensor maintains a good linear relationship in the range of 5 pg/mL to 10 ng/mL, with a LOD as low as 0.5 pg/mL. Wang et al. [105] developed a new colorimetric nano biological platform for the efficient and highly sensitive capture of circulating tumor cells (CTC), in which the MoS2 NSs surface is modified with two kinds of aptamer functionalized PH sensitive heterochromatic dyes used as a visual detection chip, which has good PH sensitivity and high dyeing ability.

4.2. ECL

ECL is a special form of chemiluminescence caused by the redox between electrogenerated high-energy radicals [106]. It does not rely on external light excitation and avoids the adverse effects of self-luminous and light scattering [107]. Therefore, it has the characteristics of precise response, easy control, low noise background signal, high sensitivity, good repeatability, and wide linear range, and has become a powerful tool for biomarkers detection and clinical diagnosis in recent years [108,109]. MoS2 can effectively improve the rate of electron transfer, and is emerging in the construction of ECL sensing platform for cancer biomarkers [110]. Zhang et al. [111] used ordered mesoporous carbon-MoS2 (OMC-MoS2) as a sensing platform and Cu2O@OMC-Ru (bpy)32+ as signal tags to develop a sandwich ECL immunosensor for the detection of AFP (Figure 5c). As we know, MoS2 NSs are easy to agglomerate, resulting in loss of activity, and the synergistic effect of nanocomposites can offset this loss of activity. OMC exhibits excellent electrocatalytic performance due to its ordered pore structure, high specific surface area, and high porosity [112]. Therefore, OMC-MoS2 can synergistically increase the effective surface area and conductivity to improve sensor sensitivity. The ECL detection range of AFP is 0.1 pg/mL-10 ng/mL, with a LOD of 0.011 pg/mL (S/N=3). Liu et al. [113] synthesized MoS2 NSs by the hydrothermal method, enhanced the electrochemiluminescence signal of sulfur doped boron nitrogen quantum dots (QDs) by using its strong surface plasmon coupling (SPC) light absorption effect in visible and near-infrared regions, and constructed an ECL sensing platform amplified by hybrid Chain reaction (HCR) for hepatitis C virus (HCV) genetic testing (Figure 5d).

4.3. Fluorescence

Fluorescence analysis is an advanced analytical method with high sensitivity, selectivity, and practicality, which can qualitatively and quantitatively analyze the changes in fluorescence intensity, emission spectrum, and fluorescence molecular lifetime of substances [114]. Due to the strong adsorption capacity and wide absorption spectrum of MoS2 NSs to ssDNA, MoS2 NSs can quench fluorescent groups with different emission wavelengths, showing unique advantages in the construction of fluorescent biosensor platforms [115]. Liang et al. [116] built a fluorescence sensing platform for the hepatocellular carcinoma (HCC) biomarker GP73 based on the Förster resonance energy transfer (FRET). Among them, utilizing synergistic effect of the MoS2@rGO composites as a fluorescence receptor further enhanced the quenching effect, and the nitrogen doped graphene QDs modified by GP73 aptamer were used as fluorescence donors. The detection range was 5 ng/mL to 100 ng/mL, and the LOD was 4.54 ng/mL (S/N=3). It also showed good detection effect in human serum. Wang et al. [117] designed QD molecular beacons (QD-MBs) functionalized MoS2 fluorescent probe (QD-MB@MoS2) for dual detection of two kinds of miRNAs related to multiple myeloma (MM), with the LOD as low as fM level, realizing ultra-high sensitivity detection (Figure 6a). In addition, when the MoS2 crystal becomes very thin, the transition from the indirect bandgap to the direct bandgap will produce strong fluorescence [118]. MoS2 QDs have strong quantum confinement and edge effects and other photoelectric properties, and are widely used in fluorescence sensing, catalysis, biological imaging and other fields [119]. Ge et al. based on the quenching of MoS2 QDs by the inner filter effect (IFE) and rolling circle amplification (RCA) technology, constructed a label-free and highly sensitive miRNA fluorescence detection platform with high selectivity and satisfactory recovery [119].

4.4. SERS

SERS technology can provide molecular fingerprint information, has high sensitivity and specificity, and does not cause damage to the sample, which is considered as a promising analytical technology in the field of disease analysis [120]. The SERS sensor composition mainly include substrates, target detection substances, and SERS capture probes. MoS2 has been applied in the preparation of SERS capture probes due to its large specific surface area, stability, and excellent catalytic performance. Engine et al. [121] developed a SERS sandwich immunosensor for ultra sensitive detection of AFP (Figure 6b). Among them, MoS2 is modified by monoclonal antibody as the capture probe of AFP, and its high surface area and adsorption capacity for biomolecules make the sensing interface more stable. The SERS immunosensor based on Au@AgNCs/MoS2 nanocomposites has a good linear response in the range of 1 pg/ml to 10 ng/mL, with a LOD as low as 0.03 pg/mL. Pan et al. [122] developed a sensitive and direct SERS aptasensor for detecting gastric cancer exosomes. AuNSs-decorated MoS2 NSs (MoS2-AuNSs) surface were assembled with ROX-labeled aptamers (ROX-Apt) used as nano probes to achieve ultra sensitive capture of exosomes (Figure 6c). This sensor quantitatively detects gastric cancer exosomes over a wide range of SERS signals (55-5.5×105 particles/μL), with a LOD as low as 17 particles/μL, which provides a prospective platform for the early diagnosis of gastric cancer. In addition, Hilal et al. [123] developed a sandwich-type SERS immunosensor for sensitive detection of CEA, which has good selectivity and stability and is well applied in clinic.

4.5. SPR

SPR provides a non-invasive and label-free method to detect analytes. MoS2 has a large absorption coefficient and high refractive index at 500nm, whose structure is conducive to the propagation of surface plasma. Such photoelectric characteristics enhance the SPR signals and improve the sensitivity of the sensor [124]. Therefore, the modification of MoS2 is also applied in SPR sensors for cancer biomarkers detection. Chiu et al. [125] prepared MoS2 by the liquid-phase exfoliation and covalently functionalize it to form carboxyl-functionalized MoS2 (carboxyl-MoS2) acting as a signal amplification sensing modification layer. The carboxylation modification effectively improved the sensitivity of the SPR sensor. The SPR chip based on carboxyl-MoS2 is used to specifically detect the lung cancer-associated biomarker cytokeratin 19 fragment (CYFRA21-1),which shows a wide linear range (0.05 pg/mL-100 ng/mL) and low LOD (0.05 pg/mL), and has good specificity, selectivity, sensitivity and affinity. Compared with traditional SPR bare gold chips, the SPR chip have many characteristics, such as unique glycan matrix structure, high surface area carboxylic acid groups, and excellent biological affinity. In addition to the above sensing methods, other sensing methods based on MoS2 are listed in the Table 2 to detect various cancer biomarkers.

5. Miscellaneous biosensors for cancer biomarkers detection based on MoS2

In addition to the two main types of cancer biomarker sensing platforms based on optics and electrochemistry, this section covers some other types of cancer biomarker sensors based on MoS2. MoS2 has the characteristics of direct bandgap, excellent switching ratio and high carrier mobility [134], which makes the MoS2 field effect transistor (FET) biosensor have the advantages of high sensitivity, label-free biological detection, system integration and easy manufacturing. Recently, Shi et al. [135] used 2D carbon-coated MoS2 NRs to form overlapping hybrid structure (MoS2@C), combining with HCR, 3D DNA walker and DNA hexahedron nano framework, which established a novel fourfold amplification and self-powered intelligent sensing platform for the ultra sensitive colorimetric/electrochemical dual-mode detection of tumor suppressor miRNAs in HCC (Figure 7a). As a hollow network structure, MoS2@C can extend the interlayer distance, not only improving the stability of the materials, but also providing more enzymes and probes binding sites. This sensor quantifies concentration of miRNAs by measuring the open circuit voltage and color changes of MBs, making it an efficient, sensitive, and highly specific sensing method. Wang et al. [136] mixed metal and semiconductor to make MoS2 composite (1T-MoS2) as an excellent substrate with high conductivity and electronic density of state, and combined it with the 2D graphitic carbon nitride (g-C3N4) to build a recyclable immunoassay platform for CA125 (Figure 7b), with the LOD as low as 4.96×10−4 IU/mL. Basing on the excellent electronic properties and high specific recognition ability of MoS2 NSs, Yang et al. [137] constructed a FET sensor array to detect the bladder cancer biomarkers nuclear matrix protein 22 (NMP22) and cytokeratin 8 (CK8), and achieved ultra sensitive detection in a wide linear range (10−6-10−1 pg/mL), with LOD as low as 0.027 aM and 0.019 aM (Figure 7c). Zhang et al. [138] functionalized MoS2 FET by coupling DNA tetrahedron and biotin-streptavidin, and detected PSA in the range of 1 fg/mL-100 ng/mL, and has broad development prospects in the field of real-time detection (Figure 7d). In addition to the above sensing methods, other sensing methods based on MoS2 are listed in the Table 3 to detect various cancer biomarkers.

6. Discussion and Outlook

As the representative of TMDs, unique bandgap adjustable layered structure of MoS2 has shown excellent optical, electronic and mechanical properties in the construction of sensing interfaces, and has further expanded the application of MoS2 as a sensing electrode in different functionalization processes. It is a promising nanomaterial to replace GO and other semiconductor devices. According to the above, the composite-based sensing interfaces built on MoS2 have been widely used in the detection of different cancer biomarkers. These sensing platforms have shown good sensitivity, specificity and reproducibility, comprehensively proving the great potential of MoS2 in early cancer screening. However, MoS2 still faces severe challenges and further development:
Since the growth process of MoS2 is uncontrollable, how to reduce the influence of impurities and lattice defects and find a large-scale and high-quality synthesis method are the fundamental issues of MoS2. 2D MoS2 has the defect of easy aggregation, which leads to the reduction of electrochemical activity. Accurate control of the synthesis of MoS2 with uniform thickness, ideal size and colloidal stability still needs further exploration. Although these shortages can be improved by modifying MoS2 with molecules, nanoparticles, or single-atom sites to form composites, achieving controllable parameters such as shape, size, charge, stability, and surface chemistry during the design process remains a major challenge [145]. Therefore, advanced synthesis techniques are needed to address these issues, such as exploring surface constrained synthesis methods and exploring better exfoliative conditions using material informatics prediction methods [146]. The covalent/non-covalent functionalization of MoS2 is a powerful tool to improve dispersion and stability, and effectively expand its application by adjusting physical properties or adding new attributes [147]. For example, changing the MoS2 ratio of 2H and 1T crystal structures by inducing defects or introducing additional negative charges, as well as changing the MoS2 bandgap through doping, embedding, and other methods [37]. By using these approaches, MoS2 can be promoted to achieve low-cost, reliable, and large-scale production, which will effectively expand the construction and application capabilities of composite-based sensing interfaces based on MoS2. These new developments will drive different composite-based sensing interfaces based on MoS2 into a new era.
The conversion of MoS2 between different dimensions makes its characteristics and applications rich, such as semiconductor, metal or superconducting materials. For example, 2H-MoS2 and 3R-MoS2 can be used for dry lubricating oil [148]. The nonlinear optical properties of 3R-MoS2 can be used for quantum measurements and nonlinear optical quality sensing in the biomedical field. Although MoS2 shows good electronic properties, compared with silicon, its electron mobility is lower and its bandgap is higher, which still faces many problems in the construction of MoS2 FET sensors. The conductivity of MoS2 NSs is affected by temperature and thickness, which increases with increasing temperature and decreases with increasing thickness until it reaches 3D structure [149]. Furthermore, MoS2 also has good characteristics of electron-spin and magnetoresistance. The research shows that MoS2 has half-metallic ferromagnetism when doped with Sc, and has a unified spin-polarization value, which is conducive to the development of spintronics [150]. The key factor for the wide application of MoS2 in optoelectronics is that it has an adjustable bandgap that changes with size and structure. The change of the bandgap dimension leads to the change of photoluminescence characteristics. MoS2 QDs have a higher bandgap than MoS2 NSs, whose optical properties can be changed by adjusting the size, or the photoluminescence intensity and emission rate can be enhanced according to the light-matter interaction. MoS2 can realize broadband detection from visible light to far infrared, which is of great significance for safety, biosensors and thermal imaging, but its responsivity and detection rate are poor due to poor light absorption and large dark current [151]. We also found that the quenching ability of MoS2 is easily affected by water and oxygen in the medium. Additionally, although MoS2 has good biocompatibility, bioabsorption, anti-cancer and antibacterial effects in catalytic and biological activity applications, it also has high toxicity [152].
In this work, the applications of electrochemical and optical sensing platforms based on MoS2 in the field of early cancer diagnosis are reviewed. In fact, MoS2 shines brightly in many fields with its rich and colorful excellent characteristics. As an example, MoS2 is a suitable battery electrode material, can be used for hydrogen evolution reactions, has great application prospects in biomedical fields such as cancer treatment and relevant fields of the Internet of things, and even performs a certain function in emerging technological fields such as microwave and terahertz technology. Besides, the miniaturization of sensing technology is of great significance for point of care testing (POCT). Now, with the popularity of miniaturized electronic devices, wearable, portable devices, electronic skin and other emerging technologies have been developed rapidly. Nowdays, with the popularity of miniaturized electronic devices, wearable, portable devices, electronic skin and other emerging technologies have been developed rapidly. MoS2, with its good mechanical properties, has become the best candidate material for flexible sensors that can be attached to the skin to achieve non-invasive detection of biomarkers in body fluids, thus minimizing skin irritation and making it easy to measure [153]. The detection of cancer biomarkers in sweat and other bodily fluids (such as saliva and urine) based on MoS2 flexible sensing interfaces needs further development, which cannot be separated from the development of electronic circuits, wireless communication units, and power supply systems.

7. Conclusion

In this review, we addressed the application of electrochemical and optical sensing platforms based on MoS2 in the field of early cancer diagnosis, explored the improvement and application of MoS2 synthesis process and material properties in the construction of biosensor platforms, and focused on the excellent characteristics of MoS2 and its composites in the construction of electrochemical and optical sensing platforms and their application in the field of cancer biomarkers detection. Although MoS2 still faces great challenges in synthesis technology, improving dispersion and conductivity, it has proven that unique excellent characteristics of MoS2 have great potential in the field of biosensors.

Author Contributions

Ziyue Qin: Literature research and collation, Conceptualization, Methodology, Data curation, Writing-original draft; Jiawei Zhang: Information access, Writing-revising; Shuang Li: Structural design, Writing-review & editing, Supervision.

Funding

This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFF1202700), the National Natural Science Foundation of China (Grant No. 82001922), the HongKong Scholars Program (Grant No. XJ2021034).

Abbreviations

AuNPs, gold nanoparticles;
rGO, reduced graphene oxide;
PDDA, poly dimethyl diallyl ammonium chloride;
Ag/AgCl, silver/silver chloride;
ITO, indium tin oxide;
AMACR, alpha-methylacyl-CoA racemase;
NaBH4, sodium borohydride;
4-NP, 4-nitrophenol;
ssDNA, single strand DNA;
AgNCs, gold nanocubes;
AuNS, gold nanostars;
CTC, circulating tumor cells;
PD-1, programmed cell death protein 1;
CYFRA21-1, cytokeratin 19 fragment (1);
T3, triiodothyronine;
DSN, duplex-specific nuclease.

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Figure 1. (a) Various crystal structures of MoS2 (1T, 2H, 3R, 2T) [34]. Copyright 2014, Elsevier. (b) Electronic band structure diagram of MoS2 with Different Thickness [40]. Copyright 2011, American Physical Society.
Figure 1. (a) Various crystal structures of MoS2 (1T, 2H, 3R, 2T) [34]. Copyright 2014, Elsevier. (b) Electronic band structure diagram of MoS2 with Different Thickness [40]. Copyright 2011, American Physical Society.
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Figure 2. Synthesis Methods of MoS2 [23,49]. Copyright 2017, Elsevier. Copyright 2012, Springer Nature.
Figure 2. Synthesis Methods of MoS2 [23,49]. Copyright 2017, Elsevier. Copyright 2012, Springer Nature.
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Figure 3. Examples of potentiometric sensors used for detecting various cancer biomarkers. (a) Optimized structure of 2H-MoS2 and 1T-MoS2 (upper plate) and schematic diagram of using Pt NWs arrays as nanopillars in ultra-thin MoS2 films (lower plate) [73]. Copyright 2020, Wiley. (b) Schematic illustration for the synthesis of the AuNPs/MoS2/rGO nanocomposite and nucleolin electrochemical aptasensor strategy [75]. Copyright 2020, Elsevier. (c) Schematic diagram of highly sensitive detection of CEA based on rGO/MoS2@polyaniline nanosheets of 3D arrays [77]. Copyright 2020, Elsevier. (d) Schematic illustration of the fabrication and PSA detection process of the EI [78]. Copyright 2020, Springer Nature.
Figure 3. Examples of potentiometric sensors used for detecting various cancer biomarkers. (a) Optimized structure of 2H-MoS2 and 1T-MoS2 (upper plate) and schematic diagram of using Pt NWs arrays as nanopillars in ultra-thin MoS2 films (lower plate) [73]. Copyright 2020, Wiley. (b) Schematic illustration for the synthesis of the AuNPs/MoS2/rGO nanocomposite and nucleolin electrochemical aptasensor strategy [75]. Copyright 2020, Elsevier. (c) Schematic diagram of highly sensitive detection of CEA based on rGO/MoS2@polyaniline nanosheets of 3D arrays [77]. Copyright 2020, Elsevier. (d) Schematic illustration of the fabrication and PSA detection process of the EI [78]. Copyright 2020, Springer Nature.
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Figure 4. Examples of amperometric/impedance/PEC sensors used for detecting various cancer biomarkers. (a) Schematic diagram of ultrasensitive electrochemical immunosensor for AFP detection based on MoS2@Cu2O-Au [79]. Copyright 2019, Elsevier. (b) Schematic illustration of electrochemical immunosensor based on MoS2 NFs/Au@AgPt YNCs as signal amplification label for sensitive detection of CEA [80]. Copyright 2019, Elsevier. (c) Schematic representation of BSA/anti-TNF-ɑ/MoS2 NFs/ITO immunoelectrode fabrication [82]. Copyright 2022, Elsevier. (d) Schematic illustration for self-assembly of MoS2/PDDA hybrid film, microfluidic chip fabrication, anti-AFP immobilization and electrochemical detection of AFP [83]. Copyright 2020, Elsevier. (e) Charge-transfer mechanism in MoS2/Au/GaN and the AFP detection schematic illustration of the PEC sensor [84]. Copyright 2021, American Chemical Society. (f) Schematic illustration of the stepwise fabrication of ZnS/C/MoS2 nanocomposite and the enhancement effect on photocurrent response [85]. Copyright 2019, Wiley.
Figure 4. Examples of amperometric/impedance/PEC sensors used for detecting various cancer biomarkers. (a) Schematic diagram of ultrasensitive electrochemical immunosensor for AFP detection based on MoS2@Cu2O-Au [79]. Copyright 2019, Elsevier. (b) Schematic illustration of electrochemical immunosensor based on MoS2 NFs/Au@AgPt YNCs as signal amplification label for sensitive detection of CEA [80]. Copyright 2019, Elsevier. (c) Schematic representation of BSA/anti-TNF-ɑ/MoS2 NFs/ITO immunoelectrode fabrication [82]. Copyright 2022, Elsevier. (d) Schematic illustration for self-assembly of MoS2/PDDA hybrid film, microfluidic chip fabrication, anti-AFP immobilization and electrochemical detection of AFP [83]. Copyright 2020, Elsevier. (e) Charge-transfer mechanism in MoS2/Au/GaN and the AFP detection schematic illustration of the PEC sensor [84]. Copyright 2021, American Chemical Society. (f) Schematic illustration of the stepwise fabrication of ZnS/C/MoS2 nanocomposite and the enhancement effect on photocurrent response [85]. Copyright 2019, Wiley.
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Figure 5. Examples of colorimetric/ECL sensors used for detecting various cancer biomarkers. (a) Schematic illustration of the colorimetric biosensor based on aptamer-modified MoS2 NSs for CEA protein detection [103]. Copyright 2020, RSC Pub. (b) Preparation of MoS2-AuNPs nanohybrids and Ab-MoS2-AuNPs nanoprobes, and schematic illustration of the colorimetric sensor for CEA detection [104]. Copyright 2019, American Chemical Society. (c) Schematic illustration of the sandwich-configuration ECL immunoassay based on Cu2O@OMC-Ru (bpy)32+ and OMC-MoS2 for determination of AFP [111]. Copyright 2020, Springer Nature. (d) The HCR-based sensing process and distance-dependent plasmon-enhanced ECL for HCV detection [113]. Copyright 2020, Elsevier.
Figure 5. Examples of colorimetric/ECL sensors used for detecting various cancer biomarkers. (a) Schematic illustration of the colorimetric biosensor based on aptamer-modified MoS2 NSs for CEA protein detection [103]. Copyright 2020, RSC Pub. (b) Preparation of MoS2-AuNPs nanohybrids and Ab-MoS2-AuNPs nanoprobes, and schematic illustration of the colorimetric sensor for CEA detection [104]. Copyright 2019, American Chemical Society. (c) Schematic illustration of the sandwich-configuration ECL immunoassay based on Cu2O@OMC-Ru (bpy)32+ and OMC-MoS2 for determination of AFP [111]. Copyright 2020, Springer Nature. (d) The HCR-based sensing process and distance-dependent plasmon-enhanced ECL for HCV detection [113]. Copyright 2020, Elsevier.
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Figure 6. Examples of fluorescence/SERS sensors used for detecting various cancer biomarkers. (a) Schematic illustration of dual miRNAs detection by QD-MB@MoS2 fluorescent probes [117]. Copyright 2022, Elsevier. (b) Schematic illustration of the SERS immunosensor based on Au@AgNCs/MoS2 nanocomposites [121]. Copyright 2021, American Chemical Society. (c) Fabrication of MoS2-based aptasensor for exosomes detection [122]. Copyright 2022, Elsevier.
Figure 6. Examples of fluorescence/SERS sensors used for detecting various cancer biomarkers. (a) Schematic illustration of dual miRNAs detection by QD-MB@MoS2 fluorescent probes [117]. Copyright 2022, Elsevier. (b) Schematic illustration of the SERS immunosensor based on Au@AgNCs/MoS2 nanocomposites [121]. Copyright 2021, American Chemical Society. (c) Fabrication of MoS2-based aptasensor for exosomes detection [122]. Copyright 2022, Elsevier.
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Figure 7. (a) Creation of ultrasensitive dual-mode approach based on self-powered sensor detecting liver cancer makers [135]. Copyright 2023, Elsevier. (b) Fabrication of Fe3O4@MoS2 composites and g-C3N4 NSs as well as the protocol of recyclable SERS-based sandwich immunoassay [136]. Copyright 2023, Elsevier. (c) Schematic illustration of MoS2 NSs-based FET sensor array for simultaneous detection of NMP22 and CK8 [137]. Copyright 2020, Springer Nature. (d) Surface functionalization and electrical characterization of the MoS2 FET device. Schematic diagram showing the 3D structure of the functionalized MoS2 biosensor (left plate). Flow chart of the device functionalization process (right plate) [138]. Copyright 2021, Elsevier.
Figure 7. (a) Creation of ultrasensitive dual-mode approach based on self-powered sensor detecting liver cancer makers [135]. Copyright 2023, Elsevier. (b) Fabrication of Fe3O4@MoS2 composites and g-C3N4 NSs as well as the protocol of recyclable SERS-based sandwich immunoassay [136]. Copyright 2023, Elsevier. (c) Schematic illustration of MoS2 NSs-based FET sensor array for simultaneous detection of NMP22 and CK8 [137]. Copyright 2020, Springer Nature. (d) Surface functionalization and electrical characterization of the MoS2 FET device. Schematic diagram showing the 3D structure of the functionalized MoS2 biosensor (left plate). Flow chart of the device functionalization process (right plate) [138]. Copyright 2021, Elsevier.
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Table 1. Electrochemical biosensors for cancer biomarkers detection based on MoS2.
Table 1. Electrochemical biosensors for cancer biomarkers detection based on MoS2.
Method Analytes Electrode/Label Linear range LOD Ref.
Chronoamperometry AMACR Pt NWs array@2H-MoS2/SPE 0.70 ng/µL-12.50 ng/µL 0.5 pg/µL [73]
CV CEA Ab/rGO/MoS2@PANI/GCE 0.001 ng/mL-80 ng/mL 0.3 pg/mL [77]
CV PSA Ab/ce-MoS2/AgNR/SPE 0.1 ng/mL-1000 ng/mL 0.051 ng/mL [78]
DPV CEA Ab/MoS2-PBNCs/GCE 0.005 ng/mL-10 ng/mL 0.54 pg/mL [86]
DPV CEA Ag/MoS2@Fe3O4-Ab2/CEA/Ab1/Ag/MGCE 0.0001 ng/mL-20 ng/mL 0.03 pg/mL [87]
DPV miRNA-182 ssRNA/MoS2/Ti3C2/GCE 1 fM-0.1 nM 0.43 fM [88]
DPV CEA MoS2-AuNPs/HRP-Ab2/CEA/Ab1/MoS2-AuNPs/GCE 10 fg/mL-1 ng/mL 1.2 fg/mL [89]
DPV Nucleolin TNA/AuNPs/MoS2/rGO/GCE 0.5 nM-1.0 μM 0.16 nM [75]
DPV CEA Ab/Pd@Pt/MoS2-Gr/GCE 0.00001 ng/mL-100 ng/mL 0.005 pg/mL [90]
DPV CA125 Ab/CuBTC@MoS2-AuNPs/SPE 0.5 mU/mL-500 U/mL 0.5 mU/mL [91]
DPV anti-retroviral agent indinavir ZnO NRs/MoS2 NSs/SPE 0.01-0.66 μM &
0.66-7.88 μM		 0.007 μM [92]
SWV CEA CeO2-MoS2-Pb2+-Ab2/CEA/Ab1/AuNPs/GCE 0.001 ng/mL-80 ng/mL 0.3 pg/mL [93]
Amperometry CEA Ab/Ag/MoS2/rGO/GCE 0.01 pg/mL-100 ng/mL 1.6 fg/mL [94]
Amperometry HBeAg Au@Pd/MoS2@MWCNTs-Ab2/HBeAg/Ab1/p-GO@Au/GCE 0.1 pg/mL-500 pg/mL 26 fg/mL [95]
Amperometry AFP MoS2@Cu2O-Au-Ab2/AFP/Ab1/AuNPs/GCE 0.1 pg/mL-50 ng/mL 0.037 pg/mL [79]
Amperometry AFP Ab/Pt NDs/PDDA/MoS2@PPy NTs/GCE 50 fg/mL-50 ng/mL 17 fg/mL [96]
Amperometry CEA MoS2 NFs/Au@AgPt YNCs
-Ab2/CEA/Ab1/AuTNPs/GCE		 10 fg/mL-100 ng/mL 3.09 fg/mL [80]
EIS CML pDNA/PANI-MoS2/ITO 10−17 M-10−6 M 3×10−18 M [97]
EIS AFP Ab/MoS2/PDDA/Ag/AgCl wire 0.1 ng/mL-10 ng/mL 0.033 ng/mL [83]
EIS miRNA-21 cDNA/pd-MoS2@β-FeOOH/Au 1 fM-5 nM 0.11 fM [81]
EIS TNF-ɑ MoS2 NFs 0.01-200 pg/ml 0.202 pg/ml [82]
PEC CEA ALP-Au-Ab2/CEA
/Ab1/ZnS/C/MoS2/GCE		 2.0 pg/mL-10.0 ng/mL 1.30 pg/mL [85]
PEC SCCA Ab/AuNPs/C/MoS2/GCE 0.005 ng/mL-8 ng/mL 1.8 pg/mL [98]
PEC AFP DNA/Au/GaN 1.0 ng/mL-150 ng/mL 0.3 ng/mL [84]
PEC MCF-7 cells PM6:Y6/anti-EpCAM-MNs
/Au NPs/Au-aptamer		 10-10000 cell/mL 9 cell/mL [99]
Table 2. Optical biosensors for cancer biomarkers detection based on MoS2.
Table 2. Optical biosensors for cancer biomarkers detection based on MoS2.
Method Analytes Electrode/Label Linear range LOD Ref.
Colorimetry CEA Au NPs-MoS2-Ab2/
CEA/Ab1/MoS2-Au NPs		 5 pg/mL-10 ng/mL 0.5 pg/mL [104]
Colorimetry CEA DNA/MoS2 NSs 50 ng/mL-1000 ng/mL 50 ng/mL [103]
Colorimetry CTC TP/SYL3C-MoS2 5-104cells/mL 2 cells/mL [105]
ECL CEA Ab/MOF-545-Zn@MQDs/GCE 0.18 ng/mL-1000 ng/mL 0.45 pg/mL [126]
ECL PSA GOD-SiO2-Ab2/PSA
/Ab1/MoS2-AuNPs/GCE		 0.5 pg/mL-10.0 ng/mL 0.20 pg/mL [127]
ECL HCV gene S-BN QDs-hairpin DNA2 (H2)/MoS2 Ns 0.5 pmoL/L-1 nmoL/L 0.17 pmoL/L. [114]
ECL HPV 16 DNA Zn-doped MoS2 QDs & QD-DNA/reductive Cu(I) particles 0.1 nmolL-200 nmolL 0.03 nmol/L [128]
ECL miRNA-210 S dots/Au NP@MoS2 NSs 0.1 pM-10 nM 0.03 pM [129]
ECL miRNA-21 luminophore/MoS2 QDs@Zeolitic Imidazolate 2 Framework-8 Buffer (0.1 mM PBS), co-reactant (2 mM H2O ) 14.6 aM [130]
Fluorescence CA15-3 DNA/MoS2 NSs 0.01 U/mL-0.1 U/mL 0.0039 U/mL [131]
Fluorescence PD-1 MoS2-NFP 125-8000 pg/mL 85.5 pg/mL [132]
Fluorescence miRNA-155 & miRNA-150 QD-MB @MoS2 10 fM-1 nM 7.19 fM &
5.84 fM		 [118]
SERS CEA MoS2 NFs@Au NPs/MBA-Ab2/CEA
/Ab1/Fe3O4 NPs@Au NPs/
d-Ti3C2TX Mxene		 0.0001 ng/mL-100.0 ng/mL 0.033 pg/mL [125]
SERS CA19-9 R6G-tagged MoS2 NF 5×10−3-100 IU/mL 3.43×10−4 IU/mL [133]
SERS exosomes MoS2-AuNSs/ROX-Apt 55-5.5×105 particles/μL 17 particles/μL [124]
SPR CYFRA21-1 Ab/COOH-MoS2/Au/Cr/BK7 0.05 pg/mL-100 ng/mL 0.05 pg/mL [125]
Table 3. Miscellaneous biosensors for cancer biomarkers detection based on MoS2.
Table 3. Miscellaneous biosensors for cancer biomarkers detection based on MoS2.
Method Analytes Electrode/Label Linear range LOD Ref.
FET array NMP22 & CK8 MoS2 NSs-FET 10−6-10−1 pg/mL 0.027-0.019 aM [137]
DeMEA/
microfluidic		 exosome GASI microfluidic channel/anti-EpCAM 1×102-1×109 exosomes/μL 17 exosomes/μL [139]
EIS/CV T3 Au-MoS2/anti-T3 electrodes 0.01-100 ng/mL 2.5 pg/mL [140]
SAW CEA AuNP–MoS2-rGO/PI 0.1 ng/ml-80 ng/ml. 0.084 ng/ml [141]
bio-FET PSA MoS2/B-SA system with DNA tetrahedron 1 fg/mL-100 ng/mL (PBS)
1 fg/mL-100 ng/mL (serum)		 1 fg/mL [138]
Paper-Based/DPV miRNA-155
miRNA-21		 AuNPs/RGO/PE
AuNPs/MoS2/PE		 33.8 nM-135.3 nM
135.6 nM-406.8 nM		 12.0 nM
25.7 nM		 [142]
Microfluidic/
electrochemical/visual		 miRNA-141 Bi2S3@MoS2 NFs/CeO2 10 fM-1 nM
0.5 fM-1 nM		 0.12 fM
2.65 fM		 [143]
signal amplification/
3D DNA walker		 microRNA-199a AuNPs/MoS2@C 0.0001-100 pM 4.94 amol/L [135]
SERS/ELISA ferritin MoS2 @Fe3O4/BP 10-10−4 μg/mL 7.3×10−5 μg/mL [144]
SERS/ELISA CA125 Fe3O4@MoS2/g-C3N4 NSs 10−3-102 IU/mL 4.96×10−4 IU/mL [136]
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