Next Article in Journal
Txnip/Trx Is a Potential Element in Regulating O-GlcNAc Modification in Photoreceptors to Alleviate Diabetic Retinopathy
Previous Article in Journal
Recent Advances in Molecular Research and Treatment for Melanoma in Asian Populations
Previous Article in Special Issue
Graphene Nanopore Fabrication and Applications
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Advances in MXene-Based Electrochemical Sensors for Multiplexed Detection in Biofluids

1
Zoology Key Laboratory of Hunan Higher Education, College of Life and Environmental Science, Hunan University of Arts and Science, Changde 415000, China
2
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(11), 5368; https://doi.org/10.3390/ijms26115368
Submission received: 13 April 2025 / Revised: 29 May 2025 / Accepted: 2 June 2025 / Published: 3 June 2025
(This article belongs to the Special Issue Molecular Recognition and Biosensing)

Abstract

Detection of multiple analytes in biofluids is of significance for early disease diagnosis, effective treatment monitoring, and accurate prognostic assessment. Electrochemical sensors have emerged as a promising tool for the multiplexed detection of biofluids due to their low cost, high sensitivity, and rapid response. Two-dimensional transition metal carbon/nitride MXene, which has the advantages of a large specific surface area, good electrical conductivity, and abundant surface functional groups, has received increasing attention in the electrochemical sensing field. This paper systematically reviews the advances of MXene-based electrochemical sensors for multiplexed detection in biofluids, emphasizing the design of MXene-based electrode materials as well as the strategies for distinguishing multiple signals during simultaneous electrochemical analysis. In addition, this paper critically analyzes the existing challenges of MXene-based electrochemical sensors for multiplexed detection of biofluids and proposes future development directions for this field. The ultimate goal is to improve biofluid multiplexed detection technology for clinical medical applications.

Graphical Abstract

1. Introduction

Biofluids (e.g., blood, urine, sweat, tears, saliva, interstitial fluid, cerebrospinal fluid, etc.) are an important part of living organisms, which contain a wide range of components such as ions, chemical molecules, biological metabolites, proteins, nucleic acids, and even substances with cellular structure [1,2]. Generally, these components vary within a certain concentration range and their abnormal levels often reflect certain health problems. Therefore, the biofluid detection is crucial for health maintenance, disease management, and personalized treatment [2]. In fact, biofluid detection has become an indispensable part of modern medicine [3]. Conventional analytical techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), liquid chromatography/gas chromatography (LC/GC), liquid chromatography–mass spectrometry (LC-MS) and gas chromatography–mass spectrometry (GC-MS), have been commonly used for clinical biofluid analysis [4,5]. Nonetheless, these conventional techniques are limited by complex and time-consuming procedures, expensive equipment, or trained technicians, and a requirement for fixed laboratory settings. In contrast, electrochemical sensing has emerged as a promising alternative due to its cost-effectiveness, simplicity, high sensitivity and selectivity, rapid response, and potential for miniaturization [6]. More importantly, it enables on-site detection and real-time monitoring [7]. Compared to single-target detection, simultaneous detection of multiple analytes presents significant advantages of reduced sample volume, lower cost, and shorter analysis time [8]. In particular, multiplexed detection is more accurate in disease diagnosis by providing more comprehensive feedback [9]. Hence, the multiplexed electrochemical sensors are receiving increasing attention.
Electrodes, as sensing interfaces, play a crucial role in electrochemical sensing. Bare electrodes usually exhibit low sensitivity and selectivity towards analytes owing to sluggish surface dynamics [10]. Moreover, it is challenging for bare electrodes to discriminate multiple analytes [11]. To address these challenges, considerable efforts have been devoted to selecting appropriate electrode modification materials to improve the performance of electrochemical sensors. The application of various nanomaterials, such as metal nanoparticles (e.g., AuNPs, PtNPs), metal oxide nanomaterials, quantum dots, carbon nanotube/nanofibers, graphene and its derivatives, conducting polymers, metal organic frameworks, ionic liquids, transition metal dichalcogenides, MXene, etc., has significantly advanced the development of electrochemical sensors [12,13,14,15,16]. Among them, the unique physicochemical properties of MXene enable it to overcome the challenges faced by other nanomaterials in electrochemical sensing, including hydrophobicity, insufficient electrical conductivity, difficulty in surface functionalization, and limited biocompatibility, making it a highly promising material for constructing electrochemical sensors. Specifically, as a two-dimensional (2D) layered material, MXene has a large specific surface area (up to 235.6 m2/g) [17], which can provide more surface-active sites. Unlike other nanomaterials, MXene possesses abundant surface functional groups and can be regulated through different preparation methods and post-treatment strategies, making it easy for surface modification and functionalization. Furthermore, compared with other 2D materials (e.g., hydrophobic graphene and poorly conductive transition metal dichalcogenides), MXene has both high electrical conductivity (up to 2.4 × 104 S/cm) [18,19] and good hydrophilicity, which makes it more suitable for the preparation of high-performance electrochemical sensors. Finally, MXene also has good biocompatibility [20], which is essential for the reliability of electrochemical biosensors.
To date, numerous review articles have addressed the application of MXene in electrochemical sensing, which summarized its utility in the detection of environmental pollutants, food safety, biomarkers, and pathogens [21,22,23,24,25,26,27,28,29,30,31]. With the growing public demand for multiplexed detection, MXene-based electrochemical sensors for multiplexed detection have been increasingly reported since 2017. However, a systematic summary detailing the application and design strategies of MXene-based multiplexed electrochemical sensing is still lacking.
This paper systematically summarizes the application of MXene-based multiplexed electrochemical sensors for biofluid detection, emphasizing the design and preparation of MXene-based electrode materials as well as the strategies for distinguishing between different target signals. In addition, the current problems of MXene-based multiplexed electrochemical sensors for biofluid detection are analyzed, and practical recommendations for future advancements in this field are presented. The aim of this paper is to promote MXene-based multiplexed electrochemical sensors for the benefit of human health business as soon as possible.

2. Brief Introduction to MXene

Since the initial discovery of Ti3C2Tx in 2011 [32], MXene has evolved into a large family of 2D transition metal carbides, nitrides, and carbonitrides. To date, more than 45 MXene species have been experimentally synthesized [33]. MXene can be represented by the formula Mn+1XnTx, where M stands for the transition metal, X denotes carbon (C) and/or nitrogen (N), Tx represents the surface functional groups (e.g., -OH, -O, -F, and -Cl), and n is 1, 2, 3, or 4 [34,35]. Based on the value of n, the molecular structure of MXene can be classified into four categories: M2XTx, M3X2Tx, M4X3Tx, and M5C4Tx [36]. Typically, MXene is prepared by etching the A atomic layer from its parent MAX phase, in which A mainly corresponds to the elements of IIIA-VIA groups. Figure 1 shows the different structures of MXene and the constituent elements of MAX and MXene.
MXene was first produced using the HF etching method. Recognizing the hazards associated with HF, alternative approaches such as in situ HF etching (acid/fluoride salt etching) [37] and NH4HF2 etching [38] were later proposed. Subsequently, some fluorine-free preparation techniques aimed at eliminating fluorine residues have been reported, including electrochemical etching [39], alkali etching [40], molten salt etching [41], and halogen etching [42]. All of the above methods for obtaining MXene through MAX precursor etching are categorized as “top-down” methods. Furthermore, MXene can also be synthesized through “bottom-up” methods, such as chemical vapor deposition (CVD) [43], plasma-enhanced pulsed laser deposition (PEPLD) [44], template-assisted growth [45], and magnetron sputtering [46]. The “top-down” methods are currently predominant in MXene preparation, but they inevitably introduce surface functional groups and defects. In contrast, “bottom-up” methods are more attractive as they hold promise for achieving higher crystallinity [33,47], but they also suffer from the problems of expensive equipment, harsh conditions, or complicated procedures. Therefore, exploring green, simple, and efficient MXene preparation techniques is still underway. MXene obtained by the etching process exhibits an accordion-like multilayered structure, with adjacent nanosheets interconnected by hydrogen bonding and van der Waals forces. Compared to multilayered MXene, single- or few-layered MXene exhibits enhanced performance in surface area, hydrophilicity, and electrochemical activity [47]. Therefore, the etched MXene usually requires some intercalators for delamination. Specifically, certain metal cations (e.g., Li+, Na+, K+), organic compounds (urea, hydrazine, dimethylsulfoxide (DMSO), isopropyl amine (i-PrA), n-butyl amine (n-BA), tetrabutylammonium hydroxide (TBAOH), tetramethylammonium hydroxide (TMAOH), and choline hydroxide (ChOH)), or polymer molecules (polyvinyl alcohol) can be intercalated into the interlayer of MXene to expand spacing [21,48,49], and then the delamination of MXene can be forced by mechanical methods (such as sonication). It is noteworthy that in situ HF etching does not require intercalation, as the cations in the fluoride salts enable simultaneous etching and intercalation [47].

3. Strategies for Discriminating Different Target Signals in Simultaneous Electrochemical Detection

The primary challenge in simultaneous electrochemical detection is how to discriminate signals from different analytes [50,51]. Depending on the analyte, simultaneous electrochemical detection can be achieved by different strategies. For electrochemically active analytes with sufficiently different redox potentials, simultaneous detection can be performed directly. Even so, enhanced detection performance (e.g., higher sensitivity and lower detection limit) can be achieved by appropriate modification of the electrode. For electrochemically active analytes with similar redox potentials, electrode modification becomes essential to alter the kinetics of the redox reaction and, in turn, differentiate the analytes [52,53]. Typically, dopamine (DA), ascorbic acid (AA), and uric acid (UA) coexist in biofluids and show overlapping oxidation potentials on bare electrodes. By modifying the electrodes with superior electrochemical nanomaterials, the oxidation peaks of these biomolecules can be effectively separated [54]. Another feasible strategy to identify electrochemically active analytes with similar redox potential is to design multiple working electrodes. For instance, a paper-based analytical device utilizing two separate working electrodes along with a shared reference and counter electrode was developed for the simultaneous electrochemical detection of norepinephrine and serotonin [55].
For analytes that lack electrochemically activity (e.g., proteins, nucleic acids, cell), a multi-electrode or multi-label strategy can be employed to distinguish between targets [50,56,57,58]. Multi-electrode platforms mainly include chip-based and paper-based electrode arrays [8]. The multi-electrode strategy has the advantage of robustness, user-friendliness, and high sensitivity and accuracy [50,57]. However, a multi-electrode system usually requires a multi-channel electrochemical analyzer (e.g., multi-channel potentiostat), which leads to a relatively high detection cost [53]. The multi-label strategy enables simultaneous detection in a single run on one working electrode. To date, various types of labels including enzymes, redox active organic molecules, Prussian blue (PB), metal nanoparticles, metal ions, quantum dots, magnetic beads, etc., have been employed for the simultaneous detection of multiple analytes [50,52,59,60]. Horseradish peroxidase (HRP), alkaline phosphatase (ALP), laccase, and glucose oxidase (GOx) are the commonly used enzyme labels. The use of enzyme labels requires the addition of specific substrates to the testing solution [61]. Redox active organic molecules include methylene blue (MB), thionine (Thi), ferrocene (Fc), toluidine blue (TB), neutral red (NR), anthraquinone 2-carboxylic acid (AQ), etc. [59,62]. Multi-label strategy using a single electrode is characterized by its simplicity and cost-effectiveness, but it faces the challenge of electrochemical signals interfering with each other (“cross-reactivity”), which needs to be solved by selecting appropriate redox active labels [61]. Notably, multi-electrode strategy was sometimes coupled with multi-label strategy to achieve target differentiation [63,64]. A summary of the strategies for simultaneous electrochemical detection is illustrated in Figure 2, and a comparative table illustrating the advantages and disadvantages of these strategies is demonstrated in Table 1.

4. MXene-Based Electrochemical Sensors for Multiplexed Detection in Biofluids

To date, a certain number of MXene-based electrochemical sensors have been developed for multiplexed detection of various analytes in biofluids. These sensors are mainly utilized for the detection of heavy metal ions, biomarkers (electrolytes, metabolites, neurotransmitters, proteins, and nucleic acids) as well as drugs in biofluids such as sweat, urine, serum, plasma, whole blood, and saliva. Various analytical methods are employed for analyte detection, including differential pulse voltammetry (DPV), square wave voltammetry (SWV), square wave anodic stripping voltammetry (SWASV), chronoamperometry (CA), amperometry, cyclic voltammetry (CV), and potentiometry. Table 2 provides an overview of these MXene-based electrochemical sensors, detailing working electrodes, signal separation strategies, target analytes, involved biofluids, analytical methods, and performance. Some representative MXene-based electrochemical sensors for multiplexed detection in biofluids are described below.

4.1. Heavy Metal Ions

Heavy metal pollution currently poses a significant threat to human health. These toxic metal ions can bioaccumulate and eventually enter the human body along the food chain, leading to diseases of the heart, kidneys, liver, central nervous system, and reproductive system. Some of these heavy metals, such as Cu2+ and Zn2+, are essential trace elements for the human body that play an important role in maintaining physiological functions, but their excess or deficiency can also result in serious health problems. In addition, the synergistic effect and additive toxicity of multiple heavy metal ions are more pronounced than that of a single metal [92]. Therefore, the simultaneous detection of heavy metal ions within the human body is crucial for mitigating health risks.
Anodic stripping voltammetry (ASV) is the predominant analytical method used for trace detection of metal ions, consisting of two steps: deposition and stripping. In the deposition step, the target ions are reduced onto the electrode surface. Therefore, it is particularly important to select electrode materials that can effectively “attract” the target ions. In the past, mercury (Hg) was the primary material utilized for heavy metal ion detection due to its ability to form metallic alloys with various ions. However, its inherent toxicity has restricted its widespread application. Recent research efforts have focused on identifying environmentally friendly alternatives to Hg.
Hui et al. [65] prepared a flexible electrochemical sensor based on a gold (Au) electrode modified by the layer-by-layer assembly of Ti3C2Tx and multiwalled carbon nanotubes (MWCNTs) nanocomposites for the non-invasive detection of Cu2+ and Zn2+ (Figure 3). The introduced MWCNTs not only alleviate the stacking problem of Ti3C2Tx nanosheets, but they also synergize with Ti3C2Tx to improve their mutual electrochemical properties. Moreover, an environmentally friendly mercury alternative, antimony (Sb), was electrodeposited in situ to further enhance analytical performance. Using SWASV measurements, the prepared sensor exhibited good analytical performance with a wide detection range (Cu2+: 10–600 ppb, Zn2+: 350–830 ppb) and low detection limits (Cu2+: 0.1 ppb, Zn2+: 1.5 ppb), and has been successfully employed for the detection Cu2+ and Zn2+ in both sweat and urine.

4.2. Biomarkers

Biomarkers, such as electrolytes (Na+, K+), small molecules (metabolites, most neurotransmitters), and macromolecules (proteins, nucleic acids), are closely related to information about the body’s physiological state [77,93,94]. Electrolytes are necessary for the regulation of body functions such as nerve transmission, hormone secretion, muscle contraction, acid–base balance, enzyme activation, and blood pressure control [95]. Metabolite levels are important for precise screening, monitoring, and prognosis of metabolic disorders and relevant diseases [96]. Neurotransmitters are important biomarkers for various neurological disorders, such as Parkinson’s disease, Alzheimer’s disease, and depression [97]. Proteins and nucleic acids are associated with a wide range of diseases such as cancer and infectious diseases [8]. Hence, the detection of biomarkers is of significance in diagnosing diseases and monitoring the health status of individuals.

4.2.1. Small Molecules

Dopamine (DA), uric acid (UA), and ascorbic acid (AA) are always coexisting in the extracellular fluids of the central nervous system and serum in humans [98]. DA is a neurotransmitter in the central nervous system that plays an important role in message transmission. Its low levels can lead to brain disorders such as schizophrenia and Parkinson’s disease. UA is a major final product of purine metabolism, and its abnormal levels are associated with gout and other related complications. AA (also known as vitamin C) is a vital vitamin in the human diet. Its deficiency can lead to gum bleeding and scurvy, while its excessive intake can cause diarrhea, urinary stones, and stomach cramps [99]. However, the simultaneous electrochemical detection of DA and UA in biofluids is challenging because coexisting high concentrations of AA interfere with DA and UA, and the oxidation potentials of AA overlap with those of DA and UA [98]. To address this challenge, different electrode modifications have been proposed.
Murugan et al. [66] successfully prepared a 2D Ti-C-Tx-MXene mixed-phase by a facile one-step synthesis and modified it on a glassy carbon electrode (GCE) to obtain Ti-C-Tx/GCE. The obtained Ti-C-Tx/GCE exhibited excellent electrocatalytic activity and good selectivity for AA, DA, and UA. Moreover, the Ti-C-Tx/GCE achieved satisfactory results in the detection of AA, DA, and UA in human urine samples. In one study, a flexible MXene-based electrochemical sensor was developed for the simultaneous detection of AA, DA, and UA [67]. To prepare the sensor, three-dimensional (3D) laser-scribed porous graphene (LSG) was first functionalized with Ti3C2Tx MXene via a C-O-Ti covalent crosslink to form an LSG-MXene hybrid scaffold, and then Au-Pd bimetallic nanoparticles were self-reduced on the surface of the scaffold to enhance the catalytic property. The obtained Au-Pd/MXene/LSG sensor with high sensitivity was successfully applied for the simultaneous detection of AA, DA, and UA in urine samples. In another study, Jia and colleagues synthesized a composite of TiO2 nanowires grown in situ on a Ti3C2Tx substrate (Ti3C2Tx/TiO2 NWs) by a simple alkaline process [68]. These TiO2 nanostructures not only alleviated the aggregation of Ti3C2Tx nanosheets, but they also increased the electrocatalytic activity of the MXene-based composites. By modifying GCE with Ti3C2Tx/TiO2 NWs, the obtained modified electrodes showed excellent performance in the simultaneous detection of AA, DA, and UA with low detection limits (AA: 6.61 μM, DA: 0.093 μM, UA: 0.038 μM).
Simultaneous monitoring of neurotransmitters and antioxidants is crucial for gaining valuable insights into the initiation and progression of various neurological disorders. The unique properties of MXene make it suitable for integration into hydrogel-based sensors. To this end, researchers introduced MXene into poly(ethylene glycol) diacrylate (PEGDA) to prepare a silane-functionalized MXene-PEGDA hydrogel for the simultaneous detection of DA, 5-hydroxytryptamine (5-HT) (neurotransmitters), and UA (antioxidant) [71]. Specifically, MXene was first functionalized with γ-KH570 to form acrylate-terminated MXene (Ac-MX), and then Ac-MX was mixed with PEGDA, a photoinitiator, and CaCl2 for ionic cross-linking under UV light to obtain the 3D porous MXene-PEGDA hydrogel. It is worth mentioning that the functionalization of MXene with silane molecules improved its activity and stability in the PEGDA hydrogel matrix. The specific surface area of the synthesized 3D composite hydrogel was significantly increased compared to 2D MXene, providing more collision frequencies for the target molecules (Figure 4a). As a result, the composite hydrogel exhibited excellent electrooxidation of DA, 5-HT, and UA, and achieved a wide linear detection range (DA: 2.5–200 μM, 5-HT: 1–100 μM, UA: 10–100 μM). More importantly, the silane-functionalized MXene-PEGDA hydrogel showed good selectivity for the simultaneous detection of DA, 5-HT, and UA in complex human serum samples.
Folic acid (FA) is an important water-soluble vitamin B for humans, and its deficiency can lead to health problems such as cardiovascular disease, cancers and neural tube defects in newborns [100]. In addition, the oxidation potential of FA overlaps with that of UA, hindering their simultaneous detection. Elumalai et al. [72] prepared AuNP@Ti3C2Tx composite films by spontaneously reducing AuNP on the delaminated Ti3C2Tx nanosheets, which were then modified on GCE for simultaneous detection of UA and FA. Thanks to the good synergy between Ti3C2Tx nanosheets and AuNP, the oxidation peak potentials of UA and AA were well separated (+0.35 V for UA and +0.70 V for FA). Adenine and guanine are indispensable components of nucleic acids, and their metabolic disorders lead to elevated uric acid levels. Avan et al. [73] synthesized copper and nitrogen co-doped Ti3C2Tx (Cu@N-Ti3C2Tx) and modified it on GCE for the simultaneous detection of adenine and guanine in unnatural sweat samples, with recoveries of 98% to 102%.
Real-time monitoring of chemical and biological substances in biofluids is critical for understanding human health status and implementing precise treatments, while current real-time electrochemical sensors still face several challenges, such as susceptibility to fouling, signal drifting, and short service life. To address the above issues, Liu et al. [74] fabricated an electrochemical microfluidic biosensor by replacing Ti3C2Tx-MXene-modified, screen-printed electrodes (SPEs) in a four-layer microfluidic chip, which enabled simultaneous and continuous analysis of three renal function biomarkers, namely urea, UA, and creatinine (Cre), in whole blood (Figure 4b). The detection of UA was based on the direct electrocatalytic oxidation of UA by the MXene/SPE. The detection of urea was based on the further immobilization of urease on the MXene/SPE, which catalyzed the production of NH3 from urea, resulting in a change in pH that in turn regulated the electrocatalytic oxidation of UA. The detection of Cre was based on the fact that MXene/SPE adsorbed Cu2+ and that Cre selectively formed a complex with Cu2+. The installation of a dialysis membrane in the chip avoided additional sample pretreatments. In addition, the sensor employed a ratiometric sensing strategy that adsorbed methylene blue (MB) via MXene as an internal reference signal, thereby greatly reducing signal drift.
Blood glucose (Glu) level is an important indicator of diabetes. In addition, elevated blood UA level is considered one of the best independent predictors of diabetes. Therefore, simultaneous monitoring Glu and UA levels in biofluids is crucial for health management and early diagnosis of diseases. In a study, Cu-TCPP(Fe), a metal–organic framework (MOF) with a large specific surface area, low diffusion resistance, and low conductivity, was integrated with highly conductive Ti3C2Tx-MXene. The Cu-TCPP(Fe)/MXene heterostructure was then modified on a paper-based electrode to develop a transient electrochemical sensor based on the superadditive effect mechanism of Cu-TCPP(Fe)/MXene for the simultaneous real-time detection of Glu and UA [75]. The results showed that the strong interfacial interactions between Cu-TCPP(Fe) and Ti3C2Tx greatly improved the electrocatalytic performance and reaction kinetics. The prepared sensor obtained superior performance with unprecedented high sensitivity (Glu: 1.88 aM, UA: 5.80 pM) and wide linear detection range (Glu: 0.001 nM–5 mM, UA: 0.025 nM–5 mM) for Glu and UA, as well as remarkable stability up to 100 days.
Sweat-based electrochemical sensing faces several challenges, such as the short shelf life of conventional electrodes, easy degradation of enzymes, and limited enzyme activity due to the oxygen deficiency in sweat. To address these issues, researchers proposed a stretchable, wearable, and modular biosensor, including a cover layer, a sensor layer, and a sweat uptake layer [76]. The etched pores in the cover layer allowed oxygen to freely enter the enzyme-active layer, ensuring maximized enzyme activity. The unique modular design of sensor layer made it possible to replace the specific sensing electrodes. The oxygen-enriched electrode of the sensor layer consisted of the enzyme, a CNTs-intercalated Ti3C2Tx/Prussian blue (PB) porous film, and a superhydrophobic carbon fiber substrate, forming a unique solid–liquid–gas, three-phase interface (Figure 4c). The CNTs/Ti3C2Tx/PB composites exhibited excellent conductivity and electrochemical activity, greatly improving the electrochemical performance of the sensor. As a result, the sensor realized the simultaneous detection of Glu and Lac in sweat with high sensitivity (Glu: 35.3 µA/mM·cm2, Lac: 11.4 µA/mM·cm2) and good repeatability. In addition, a pH-sensing module was incorporated to correct this pH-dependent deviation in the enzyme-based sensor. In another study, a dual-channel electrochemical sensor for real-time monitoring of glucose and lactate in sweat was prepared based on disposable highly integrated sensing (HIS) paper (Figure 4d). To prepare the HIS paper, the paper was first treated with a simple printing process and then folded into a multilayer structure, in which the MXene/methylene blue (Ti3C2Tx/MB)-active materials were modified on the working electrodes to facilitate charge migration and biomolecule immobilization. In addition, the 3D sweat diffusion path along the vertical direction of the HIS paper accelerated sweat collection and transport kinetics. The HIS paper-based sensors were demonstrated to be used for simultaneous detection of Glu and Lac with high sensitivity (Glu: 2.4 nA/μM, Lac: 0.49 μA/mM) [77].

4.2.2. Macromolecules

Developing a simple, precise, and controllable method for depositing nanomaterials onto the patterned electrode remains one of the most challenging issues in the fabrication of electrochemical biosensors. To address this issue, Sharifuzzaman et al. [78] developed an innovative electrodeposition strategy for uniformly depositing Ti3C2Tx-MXene nanosheets onto a gold dual interdigitated microelectrode (DIDμE). A task-specific ionic liquid, 4-amino-1-(4-formyl-benzyl) pyridinium bromide (AFBPB), was then introduced onto the electrode, which can tightly bind to MXene via electrostatic interaction and π–π stacking, and its aldehydic group also enabled covalent immobilization of biomolecules. Attributed to the homogeneous deposition of conductive MXene and AFBPB, the resultant immunosensor based on MXNSs-AFBPB-modified DIDμE exhibited a 7-fold enhancement in redox current compared to a bare DIDμE. Notably, the immunosensor achieved simultaneous detection of two bladder cancer biomarkers (Apo-A1 and NMP 22) with a wide linear range spanning over five orders of magnitude and low detection limits of 0.3 pg/mL (Apo-A1) and 0.7 pg/mL (NMP 22).
Interleukin-1β (IL-1β) and matrix metalloproteinases-8 (MMP-8) are considered typical salivary biomarkers for early diagnosis and progression monitoring of periodontitis. To meet the clinical need for multiplexed detection, Zhang et al. [79] designed a dual-channel microfluidic electrochemical immunosensor for the simultaneous determination of IL-1β and MMP-8. The integrated system combined a dual-channel chip with two independent SPEs, each of which was modified with iridium oxide (IrOx) nanotubes/Ti3C2Tx nanocomposites. Owing to the synergistic effects of IrOx/Ti3C2Tx nanocomposites to enhance the electron transfer kinetics, the sensor achieved wide detection ranges (IL-1β: 0.1–100 ng/mL, MMP-8: 1–200 ng/mL) and low detection limits (IL-1β: 0.014 ng/mL, MMP-8: 0.13 ng/mL). Additionally, the sensor exhibited remarkable performance in both artificial and clinicopathological saliva analysis, and was promising for point-of-care testing (POCT) for periodontitis diagnosis.
Antifouling coatings are critical for the reliability of biosensors as they prevent non-specific adsorption of interferents. In a recent study, a novel 3D porous antifouling nanocomposite was prepared, which consists of a porous framework of glutaraldehyde (GA) crosslinked with bovine serum albumin (BSA) and 1-pyrenebutyric acid (PBA)-functionalized MXene nanosheets as conductive nanofillers [80]. The oxidation-resistant Ti3C2Tx MXene nanosheets (Al-MXNs) were covalently functionalized with PBA, which facilitated the stable bonding of MXene to the porous framework (Figure 5a). The framework, with its appropriately sized pores, effectively blocked exogenous proteins and minimized interference, while the PBA-functionalized MXene improved the electrochemical lifetime. To test the reliability of the nanocomposite, a multiplexed electrochemical immunosensor was constructed based on 3D-MXting (BSA/Al-MXNs@PBA/GA), antifouling nanocomposite for the simultaneous detection of the inflammatory biomarkers C-reactive protein (CRP) and ferritin, which exhibited excellent detection limits (CRP: 6.2 pg/mL, ferritin: 4.2 pg/mL). In addition, the sensor demonstrated good selectivity and stability in whole serum.
Rapid, accurate, and cost-effective methods for multiplexed detection of infectious disease biomarkers are of great clinical significance. To this end, researchers proposed a multi-channel electrochemical immunosensor with in situ electrodeposition of a MXene/AuNPs composite on SPE [81]. As the AuNPs and MXene nanoflower enlarged the surface area and improved electron transfer efficiency, the sensor achieved highly sensitive detection of three infectious disease biomarkers with wide detection ranges (HBsAg: 0.05–1000 ng/mL, anti-HIV: 0.25–100 ng/mL, anti-TP: 0.35–140 ng/mL), and low detection limits (HBsAg: 0.01 ng/mL, anti-HIV: 0.10 ng/mL, anti-TP: 0.11 ng/mL). Notably, this is the first research that can simultaneously detect three infectious disease biomarkers from a single serum sample.
MicroRNAs are potent clinical biomarkers for early cancer diagnosis. However, sensitive multiplexed detection of microRNAs for accurate cancer diagnosis remains a challenge due to their homologous sequences and low abundance in biofluids. To address these issues, Mohammadniaei and coworkers [82] developed an electrochemical biosensor based on a home-made, screen-printed gold electrode (SPGE) by combining AuNP@MXene electrochemical signal amplification and duplex-specific nuclease (DSN)-based signal amplification strategies (Figure 5b). MXene enhanced the electrochemical signal of the electrode by nearly 4 times, attributed to its large surface area and high charge mobility. For DSN amplification, functionalized magnetic probes with MB- or Fc-labeled, single-stranded DNA (ssDNA) were designed for target-specific cleavage and redox signal generation via DSN amplification. The fabricated biosensor enabled rapid (80 min), attomolar, and simultaneous quantification of two cancer biomarkers, microRNA-21 and microRNA-141. Moreover, this developed strategy, combined with a 96-well adaptive sensing device, enabled the successful analysis of three cancer plasma samples.

4.2.3. Multi-Type Analytes

The emerging MXene-based electrochemical sensors for multiplexed detection in biofluids are no longer limited to a single type of biomarkers but have expanded to simultaneously identify multiple types. These sensors can provide more comprehensive insights for early diagnosis, real-time monitoring, and therapeutic efficacy evaluation assessment of diseases. Furthermore, this capability allows for the integrated diagnosis of multiple diseases through a single analytical platform, thereby enhancing clinical decision-making and personalized healthcare strategies.
Carbon fiber paper (CFP), a 3D carbon material made of interlaced carbon fibers, is considered as an applicable flexible substrate due to its ultra-high conductivity, rich electroactive sites, and good flexibility. In a study, the Huo group reported a flexible electrochemical biosensing platform based on a CFP-Ti3C2Tx-MoS2-sensing interface for the detection of AA, DA, UA, and microRNA in biofluids [83]. The design of Ti3C2Tx-MoS2 heterostructure uniformly loaded on CFP facilitated the enrichment of biomolecules, and thus the platform can be used for the simultaneously sensitive detection of AA, DA, and UA. Based on this, capture probes were introduced into the interface by electrodeposition of Au NPs. Combined with the hybridization chain reaction (HCR) and horseradish peroxidase (HRP)-catalyzed amplification, the platform realized the aM level microRNA detection. Notably, the platform also performed well in complex biofluids.
The new generation of textile electrodes (TEs) incorporating capacitive transducers can provide stable signal monitoring in long-term healthcare analysis. In view of this, Kalasin and Sangnuang developed a multiplexed, wearable electrochemical sensor based on sodiated polymers and MXene nanosheet-modified textile electrodes (TEs) for the potentiometric measurement of sodium ion (Na+) and the voltametric measurement of Cre in sweat [84]. To fabricate such sensors, sodiated poly(3,4-ethylenedioxythiophene) polystyrenesulfonate (PEDOT:PSS) and polypyrrole (PPy) were inserted between sodiated, nanoporous layer carbon–polyethylene glycol (PEG) and sodiated Ti3C2Tx nanosheets for the potentiometric measurement of Na+ and voltametric measurement of creatinine, respectively (Figure 6a–c). This structural design minimized electron transfer loss. In addition, an electrochemical minimizing-interference layer (MIL) was incorporated into the ion-selective membrane (ISM) and creatinine-sensing material (SM), respectively, to minimize the sweat interference. The developed wearable sensors exhibit excellent long-term stability and minimal potential drift in sweat analysis.
Flexible sweat sensors capable of detecting multi-type biomarkers can provide valuable information for understanding personal health. In a study, a novel composite, NS-TiO2@MXene-HG, consisting of nitrogen and sulfur co-doped MXene and holey graphene (HG), as well as TiO2 nanoparticles grown in situ on the MXene, was synthesized by a facile hydrothermal and then modified on a reduced graphene oxide (rGO) screen-printed electrode (rGSPE) to develop a flexible electrochemical sensor (Figure 6d). Since doped MXene and HG promoted electron transfer and increased active sites, and TiO2 enhanced electrocatalytic activity, the NS-TiO2@MXene-HG/rGSPE enabled sensitive detection of AA, UA, and DA simultaneously. In addition, a potassium ion-selective, membrane-modified electrode (K+-ISM/rGSPE) was fabricated by modifying a K+-selective membrane on rGSPE, which realized simultaneous detection of K+, AA, UA, and DA in sweat [85].

4.3. Drugs

Drug monitoring in biofliuds is essential for facilitating personalized therapy and reducing drug side effects [101]. On the one hand, because individual factors (e.g., age, gender, addictions, liver and kidney function) affect the pharmacokinetics, the actual response and therapeutic efficacy of a drug varies significantly among individuals [4]. Accurate monitoring of drug concentrations in biofluids can assist physicians in developing personalized treatment plans. On the other hand, many therapeutic drugs cause severe adverse effects, such as cardiovascular risks, cerebral risks, gastrointestinal toxicity, hepatotoxicity, and renal injuries [102]. Monitoring the drug concentration in biofluids allows for timely adjustment of drug dosages to avoid the risk of overdose. In addition, the combination of multiple drugs is becoming more common in modern medicine, such as the combination of anticancer drugs and antibiotics in cancer treatment [100], which increases the risk of drug interactions and adverse reactions. Therefore, the simultaneous detection of multiple drugs in biofluids is particularly important, which can provide comprehensive drug information for clinical treatment and improve therapeutic efficacy.
Acetaminophen (ACOP, also known as paracetamol) is a typical hepatotoxic drug widely used to treat pain and fever. Isoniazid (INZ) is another common hepatotoxic drug mainly used to treat tuberculosis. In a study, a Ti3C2Tx-MXene-modified, screen-printed electrode (Ti3C2Tx/SPE) was developed for the simultaneous determination of ACOP and INZ [86]. Ti3C2Tx/SPE exhibited excellent electrocatalytic activity for both ACOP and INZ compared to bare SPE. During the simultaneous determination of ACOP and INZ, the Ti3C2Tx/SPE obtained clearly separated ACOP and INZ oxidation peaks, as well as good analytical performance for the targets with a wide linear range (ACOP: 0.25 to 2000 μM, INZ: 0.1 to 4.6 mM). More importantly, Ti3C2Tx/SPE was able to detect ACOP and INZ in the human serum without significant interference. Studies have shown that the combination of paracetamol (PA), theophylline (TP), and caffeine (CA) is utilized for managing childbirth, treating migraine attacks, and avoiding postpartum hemorrhage. In a study, electrochemically active Ti3C2Tx MXene/MWCNT nanocomposites were prepared using microwave and ultrasonication processes and then modified on a SPE for the simultaneous determination of PA, TP, and CA in serum [87]. The prepared Ti3C2Tx-MWCNT/SPE demonstrated outstanding performance in detecting PA, TP, and CF in human samples, with good detection limits of 0.23 µM, 0.57 µM, and 0.43 µM, respectively. In another study, Ti3C2Tx@Au nanoparticles–ZnO nanoparticles@N-doped carbon (Ti3C2Tx@AuNPs-ZnO@NC) was designed for the simultaneous detection of three pharmaceutical molecules—ACOP, DA, and xanthine (XA) [88]—where the detection of DA is useful for the diagnosis of Parkinson’s disease and depression, and the detection of XA facilitates the treatment of asthma. Ti3C2Tx@AuNPs-ZnO@NC was prepared by a three-step process of etching, wet chemical treatment, and pyrolysis process (Figure 7a). Since the structural design of the few-layer Ti3C2Tx nanosheets loaded with a large number of AuNPs-ZnO@NC provided electron transport channel for electrochemical reaction, and the NC offered abundant anchoring sites for immobilizing highly active AuNPs, Ti3C2Tx@AuNPs-ZnO@NC exhibited excellent electrochemical performance for the simultaneous determination of DA, AC, and XA, with LODs of 41 nM, 59 nM, and 67 nM, respectively. In addition, Ti3C2Tx@AuNPs-ZnO@NC could be performed in human blood samples, with recoveries ranging from 93.0% to 108.5%.
Aristolochic acid (AA′) is used in traditional Chinese medicines, but it can cause severe health problems such as urinary epithelial cancer, renal tumors, and renal failure. Roxarsone (ROX) is widely used in poultry farming to gain weight, and its elevated levels can lead to neurodegenerative disorders and several types of cancers in humans. Rajaji et al. [89] prepared an electrochemical sensor based on a laser-induced graphene electrode (LGE) modified with a hybrid of MoS2 sphere and sulfur-doped Ti3C2 MXene (MoS2/S-Ti3C2) for the simultaneous detection of AA′ and ROX. The MoS2/S-Ti3C2 hybrid was synthesized by hydrothermal treatment and calcination. MoS2/S-Ti3C2/LGE exhibited good electrocatalytic performance for AA′ and ROX. In addition, the MoS2/S-Ti3C2/LGE-based sensor demonstrated satisfactory recoveries (97.00–99.00%) for the quantitative detection of AA′ and ROX in human urine and serum samples.
The combination of anticancer drugs and antibiotics is common in cancer chemotherapy, and their overdose can cause severe adverse effects in patients. Nitrofurantoin (NFT) and nilutamide (NLT) are widely used antibiotics and anticancer drugs, respectively. These two drugs have the same electroactive functional group (nitro-group), resulting in signal overlap in electrochemical detection. Therefore, it is crucial to develop novel electrode materials to separate their signals in simultaneous detection. In view of the above, Devi et al. [90] designed a nanocomposite of partially oxidized Ti3C2Tx-MXene and holey graphene oxide (p-TC/hGO) for the simultaneous electrochemical detection of NFT and NLT (Figure 7b). The p-TC/hGO nanocomposite was prepared by wet chemical and sonication processes. Since p-TC improved electrical conductivity, hGO increased specific surface area and p-TC flakes and hGO were interconnected to form a conductive network to further facilitate electron transport, p-TC/hGO provided abundant active sites and high electrocatalytic activity for NFT and NLT detection. Compared to the reported literature, the p-TC/hGO/GCE-based sensor demonstrated an outstanding analytical performance in the simultaneous detection of NFT and NLT with low LOD (NFT: 1.2 nM, NLT: 1.9 nM) and ultra-high sensitivity (NFT: 52.8 µA µM−1 cm−2, NLT: 19.5 µA µM−1 cm−2). Moreover, the accuracy and real-time application of the sensor were validated in artificial urine samples.
Carbamazepine (CBZ) is an anticonvulsant used to treat epilepsy and trigeminal neuralgia management, and its overdose can cause drowsiness, nausea, leukopenia, and other adverse reactions. Levothyroxine (LT4) is a thyroid hormone replacement drug, and its overdose may lead to risks such as allergy and myocardial infarction. Recently, a highly selective electrochemical sensor based on a MOF-71/V2C MXene hydrogel was fabricated by a solvothermal and freeze-drying method for the simultaneous detection of CBZ and LT4 in simulated serum. Combing a porous architecture, large surface area, high catalytic activity, excellent electrical conductivity, and good mechanical flexibility, the MOF-71/V2C hydrogel achieved a wide linear detection range (10 nM–100 µM for LT4 and 10 nM–500 µM for CBZ), low detection limits (5.6 nM for LT4 and 6.7 nM for CBZ), excellent selectivity against interferents, and outstanding electrochemical stability. The sensor demonstrated high sensitivity even in complex biological matrices, making it a promising platform for clinical diagnostics and therapeutic drug monitoring [91].

5. Conclusions and Outlook

In recent years, MXene-based electrochemical sensors have been successfully applied to the simultaneous detection of various biofluids, including sweat, urine, blood (whole blood, serum, and plasma), and saliva. These sensors can effectively identify a wide range of targets, such as heavy metal ions (Cu2+, Zn2+), electrolytes (Na+, K+), metabolites (UA, AA, FA, Cre, Glu, Lac, urea, purine), neurotransmitters (DA, 5-HT), protein biomarkers, nucleic acids (microRNA), and drugs (Figure 8). Using strategies including the introduction of other materials (metal nanoparticles, metal oxides, carbon nanomaterials, polymers, etc.), heteroatom doping, construction of heterostructures (e.g., MXene/MoS2, MXene/MOF), and the construction of 3D porous structures (e.g., MXene-based hydrogels), MXene-based electrode materials with high electrical conductivity, catalytic activity and anti-interference ability were produced. Combined with electrode modification, multi-electrode, or multi-label signal separation strategies, the MXene-based electrochemical sensors have made remarkable advancements in the multiplexed detection of biofluids.
However, MXene-based electrochemical sensors for simultaneous biofluid detection still face some deficiencies or challenges that need further development:
(1)
MXene is mainly synthesized through HF etching and in situ HF etching, which results in the formation of -F, -O, and -OH surface groups. These non-uniform terminations are not favorable for the effective immobilization of biorecognition elements. Furthermore, F-terminated MXene exhibit low electrical conductivity [103]. In the future, some strategies can be employed to modulate the surface groups of synthesized MXene to enhance its electrochemical properties [104]. In addition, other fluoride-free synthesis methods for MXene can be explored.
(2)
The existing studies focus on the multiplexed detection of sweat, blood, urine, and saliva, while other important biofluids, such as tears and interstitial fluid, have not yet been explored. In the future, detection methods for other biofluids should be developed to extend the application of MXene-based, multiplexed electrochemical sensors.
(3)
The current targets mainly cover electrolytes, metabolites, neurotransmitters, proteins, nucleic acids, etc., while the detection of pathogens (e.g., bacteria and viruses) is lacking. In the future, the MXene-based electrochemical sensors for the simultaneous detection of pathogens in biofluids can be further developed.
(4)
Real-time monitoring of biofluids is currently focused on SPE-based wearable sensors for sweat detection. However, real-time monitoring of other biofluids, such as interstitial fluid and blood, remains an important area for breakthrough. In the future, wearable microneedle arrays or even implantable sensors are expected to be developed for real-time monitoring of other biofluids [105].
(5)
The existing sensors are mostly confined to the simultaneous detection of two to three targets, while the high-throughput detection of more than five targets remains to be achieved. In the future, higher throughput detection can be realized through the fabrication of microelectrode arrays or integration with microfluidic technologies.
(6)
The accurate analysis of complex high-throughput data from signal interference in high-throughput electrochemical detection is a great challenge, and the introduction of machine learning techniques provides an effective solution to this problem [106]. In the future, MXene-based, high-throughput electrochemical platforms can be developed in combination with machine learning techniques for more accurate biofluid detection.
(7)
Integration of MXene-based, electrochemical multiplexed sensors into clinical POC diagnostic platforms also need to systematically address the regulatory, biocompatibility, and ethical issues [107]. Rigorous quality control and standardized procedures need to be established to ensure the reliability of the sensors in real biofluidic environments, which set high standards for long-term material performance and manufacturing processes. Biocompatibility assessment is crucial, and the potential toxicity, inflammatory response, and long-term in vivo retention effects of MXene-based materials in the target biofluidic environments must be comprehensively examined to ensure their biosafety. In addition, ethical issues related to the protection of user data privacy, the acquisition of informed consent, and the accessibility and fairness of these advanced diagnostic tools also need to be proactively addressed.
In summary, the development of the MXene-based electrochemical sensors for multiplexed detection in biofluid is still on its way. The convergence of advanced manufacturing technologies, artificial intelligence, and biomedical engineering presents unprecedented opportunities for the next-generation of MXene-based, multiplexed electrochemical sensors, and ultimately enables these sensors to truly serve real-time physiological monitoring and personalized healthcare for humans.

Author Contributions

Conceptualization, M.Y.; data curation, M.Y. and C.X.; writing—original draft, M.Y. and C.X.; writing—review and editing, M.Y. and H.L.; funding acquisition, M.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Doctoral Research Start-up Fund (No. 21BSQD43, Hunan University of Arts and Science), the Excellent Youth Project of Hunan Education Department (No. 23B0661, Hunan Provincial Department of Education), and the Natural Science Foundation of Hunan Province of China (No. 2023JJ40463, Hunan Provincial Department of Science and Technology).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Chen, L.; Yang, G.; Qu, F. Advances of aptamer-based small-molecules sensors in body fluids detection. Talanta 2024, 268, 125348. [Google Scholar] [CrossRef] [PubMed]
  2. Li, H.; Gu, S.; Zhang, Q.; Song, E.; Kuang, T.; Chen, F.; Yu, X.; Chang, L. Recent advances in biofluid detection with micro/nanostructured bioelectronic devices. Nanoscale 2021, 13, 3436–3453. [Google Scholar] [CrossRef] [PubMed]
  3. Heikenfeld, J.; Jajack, A.; Feldman, B.; Granger, S.W.; Gaitonde, S.; Begtrup, G.; Katchman, B.A. Accessing analytes in biofluids for peripheral biochemical monitoring. Nat. Biotechnol. 2019, 37, 407–419. [Google Scholar] [CrossRef] [PubMed]
  4. Krämer, J.; Kang, R.; Grimm, L.M.; De Cola, L.; Picchetti, P.; Biedermann, F. Molecular probes, chemosensors, and nanosensors for optical detection of biorelevant molecules and ions in aqueous media and biofluids. Chem. Rev. 2022, 122, 3459–3636. [Google Scholar] [CrossRef]
  5. Zhang, W.; Ren, Y.; Lin, Z.; Ouyang, Z. High-precision quantitation of biofluid samples using direct mass spectrometry analysis. Anal. Chem. 2019, 91, 6986–6990. [Google Scholar] [CrossRef]
  6. Lu, L. Recent advances in synthesis of three-dimensional porous graphene and its applications in construction of electrochemical (bio)sensors for small biomolecules detection. Biosens. Bioelectron. 2018, 110, 180–192. [Google Scholar] [CrossRef]
  7. Bansod, B.; Kumar, T.; Thakur, R.; Rana, S.; Singh, I. A review on various electrochemical techniques for heavy metal ions detection with different sensing platforms. Biosens. Bioelectron. 2017, 94, 443–455. [Google Scholar] [CrossRef]
  8. Klebes, A.; Ates, H.C.; Verboket, R.D.; Urban, G.A.; Von Stetten, F.; Dincer, C.; Früh, S.M. Emerging multianalyte biosensors for the simultaneous detection of protein and nucleic acid biomarkers. Biosens. Bioelectron. 2024, 244, 115800. [Google Scholar] [CrossRef]
  9. Pakchin, P.S.; Fathi, F.; Samadi, H.; Adibkia, K. Recent advances in receptor-based optical biosensors for the detection of multiplex biomarkers. Talanta 2025, 281, 126852. [Google Scholar] [CrossRef]
  10. Li, B.; Xie, X.; Meng, T.; Guo, X.; Li, Q.; Yang, Y.; Jin, H.; Jin, C.; Meng, X.; Pang, H. Recent advance of nanomaterials modified electrochemical sensors in the detection of heavy metal ions in food and water. Food Chem. 2024, 440, 138213. [Google Scholar] [CrossRef]
  11. Filik, H.; Avan, A.A. Review on applications of carbon nanomaterials for simultaneous electrochemical sensing of environmental contaminant dihydroxybenzene isomers. Arab. J. Chem. 2020, 13, 6092–6105. [Google Scholar] [CrossRef]
  12. Amali, R.K.A.; Lim, H.N.; Ibrahim, I.; Huang, N.M.; Zainal, Z.; Ahmad, S.A.A. Significance of nanomaterials in electrochemical sensors for nitrate detection: A review. Trends Environ. Anal. Chem. 2021, 31, e00135. [Google Scholar] [CrossRef]
  13. Liu, T.; Chu, Z.; Jin, W. Electrochemical mercury biosensors based on advanced nanomaterials. J. Mater. Chem. B 2019, 7, 3620–3632. [Google Scholar] [CrossRef]
  14. Liu, X.; Yao, Y.; Ying, Y.; Ping, J. Recent advances in nanomaterial-enabled screen-printed electrochemical sensors for heavy metal detection. TrAC Trends Anal. Chem. 2019, 115, 187–202. [Google Scholar] [CrossRef]
  15. Mohamed, A.M.; Fouad, F.H.; Fayek, G.R.; El Sayed, K.M.; Ahmed, M.N.; Mahmoud, R.Z.; El Nashar, R.M. Recent advances in electrochemical sensors based on nanomaterials for detection of red dyes in food products: A review. Food Chem. 2023, 435, 137656. [Google Scholar] [CrossRef]
  16. Uçar, A.; Aydoğdu Tığ, G.; Er, E. Recent advances in two dimensional nanomaterial-based electrochemical (bio)sensing platforms for trace-level detection of amino acids and pharmaceuticals. TrAC Trends Anal. Chem. 2023, 162, 117027. [Google Scholar] [CrossRef]
  17. Min, X.; Liu, F.; Wang, Y.; Yan, Y.; Wang, H. Synthesis and electrochemical behavior of monolayer-Ti3C2Tx for capacitive deionization. J. Cent. South Univ. 2022, 29, 359–372. [Google Scholar] [CrossRef]
  18. Jia, L.; Zhou, S.; Ahmed, A.; Yang, Z.; Liu, S.; Wang, H.; Li, F.; Zhang, M.; Zhang, Y.; Sun, L. Tuning MXene electrical conductivity towards multifunctionality. Chem. Eng. J. 2023, 475, 146361. [Google Scholar] [CrossRef]
  19. Zeraati, A.S.; Mirkhani, S.A.; Sun, P.; Naguib, M.; Braun, P.V.; Sundararaj, U. Improved synthesis of Ti3C2Tx MXenes resulting in exceptional electrical conductivity, high synthesis yield, and enhanced capacitance. Nanoscale 2021, 13, 3572–3580. [Google Scholar] [CrossRef]
  20. Mathew, M.; Rout, C.S. Electrochemical biosensors based on Ti3C2Tx MXene: Future perspectives for on-site analysis. Curr. Opin. Electrochem. 2021, 30, 100782. [Google Scholar] [CrossRef]
  21. Mohanapriya, D.; Satija, J.; Senthilkumar, S.; Ponnusamy, V.K.; Thenmozhi, K. Design and engineering of 2D MXenes for point-of-care electrochemical detection of bioactive analytes and environmental pollutants. Coord. Chem. Rev. 2024, 507, 215746. [Google Scholar] [CrossRef]
  22. Rhouati, A.; Berkani, M.; Vasseghian, Y.; Golzadeh, N. MXene-based electrochemical sensors for detection of environmental pollutants: A comprehensive review. Chemosphere 2022, 291, 132921. [Google Scholar] [CrossRef] [PubMed]
  23. Ganesh, P.-S.; Kim, S.-Y. Electrochemical sensing interfaces based on novel 2D-MXenes for monitoring environmental hazardous toxic compounds: A concise review. J. Ind. Eng. Chem. 2022, 109, 52–67. [Google Scholar] [CrossRef]
  24. Pengsomjit, U.; Alabdo, F.; Olawale, S.H.; Choowongkomon, K.; Sharma, V.K.; Darwish, I.A.; Kraiya, C. Recent advances and analytical perspectives in MXene-based electrochemical miniaturized sensors for environmental analysis and monitoring. Microchem. J. 2024, 206, 111433. [Google Scholar] [CrossRef]
  25. Umapathi, R.; Raju, C.V.; Safarkhani, M.; Haribabu, J.; Lee, H.U.; Rani, G.M.; Huh, Y.S. Versatility of MXene based materials for the electrochemical detection of phenolic contaminants. Coord. Chem. Rev. 2025, 525, 216305. [Google Scholar] [CrossRef]
  26. Seitak, A.; Luo, S.; Cai, N.; Liao, K.; Pappa, A.-M.; Lee, S.; Chan, V. Emergence of MXene-based electrochemical biosensors for biomolecule and pathogen detection. Sens. Actuators Rep. 2023, 6, 100175. [Google Scholar] [CrossRef]
  27. Karadurmus, L.S.; Kaya, I.; Cetinkaya, A.; Ozkan, S.A. New brand MXene-based electrochemical point-of-care sensors as novel diagnostic devices. TrAC Trends Anal. Chem. 2023, 165, 117145. [Google Scholar] [CrossRef]
  28. Li, T.; Shang, D.; Gao, S.; Wang, B.; Kong, H.; Yang, G.; Shu, W.; Xu, P.; Wei, G. Two-dimensional material-based electrochemical sensors/biosensors for food safety and biomolecular detection. Biosensors 2022, 12, 314. [Google Scholar] [CrossRef]
  29. Lorencova, L.; Kasak, P.; Kosutova, N.; Jerigova, M.; Noskovicova, E.; Vikartovska, A.; Barath, M.; Farkas, P.; Tkac, J. MXene-based electrochemical devices applied for healthcare applications. Microchim. Acta 2024, 191, 88. [Google Scholar] [CrossRef]
  30. Ganesan, S.; Ramajayam, K.; Kokulnathan, T.; Palaniappan, A. Recent advances in two-dimensional MXene-based electrochemical biosensors for sweat analysis. Molecules 2023, 28, 4617. [Google Scholar] [CrossRef]
  31. Kalambate, P.K.; Gadhari, N.S.; Li, X.; Rao, Z.; Navale, S.T.; Shen, Y.; Patil, V.R.; Huang, Y. Recent advances in MXene–based electrochemical sensors and biosensors. TrAC Trends Anal. Chem. 2019, 120, 115643. [Google Scholar] [CrossRef]
  32. Naguib, M.; Kurtoglu, M.; Presser, V.; Lu, J.; Niu, J.; Heon, M.; Hultman, L.; Gogotsi, Y.; Barsoum, M.W. Two-dimensional nanocrystals produced by exfoliation of Ti3AlC2. Adv. Mater. 2011, 23, 4248–4253. [Google Scholar] [CrossRef] [PubMed]
  33. Saeed, M.A.; Qamar, M.Z.; Khalid, Z.; Chamanehpour, E.; Mishra, Y.K. Two-dimensional MXenes: A route from synthesis to applications in self-powered IoT devices. Chem. Eng. J. 2024, 490, 151600. [Google Scholar] [CrossRef]
  34. Mohammadi, A.; Rosen, J.; Gogotsi, Y. The world of two-dimensional carbides and nitrides (MXenes). Science 2021, 372, eabf1581. [Google Scholar]
  35. Patil, A.M.; Jadhav, A.A.; Chodankar, N.R.; Avatare, A.T.; Hong, J.; Dhas, S.D.; Patil, U.M.; Jun, S.C. Recent progress of MXene synthesis, properties, microelectrode fabrication techniques for microsupercapacitors and microbatteries energy storage devices and integration: A comprehensive review. Coord. Chem. Rev. 2024, 517, 216020. [Google Scholar] [CrossRef]
  36. Seidi, F.; Shamsabadi, A.A.; Firouzjaei, M.D.; Elliott, M.; Saeb, M.R.; Huang, Y.; Li, C.; Xiao, H.; Anasori, B. MXenes antibacterial properties and applications: A review and perspective. Small 2023, 19, 2206716. [Google Scholar] [CrossRef]
  37. Ghidiu, M.; Lukatskaya, M.R.; Zhao, M.-Q.; Gogotsi, Y.; Barsoum, M.W. Conductive two-dimensional titanium carbide ‘clay’ with high volumetric capacitance. Nature 2014, 516, 78–81. [Google Scholar] [CrossRef]
  38. Halim, J.; Lukatskaya, M.R.; Cook, K.M.; Lu, J.; Smith, C.R.; Näslund, L.-Å.; May, S.J.; Hultman, L.; Gogotsi, Y.; Eklund, P.; et al. Transparent conductive two-dimensional titanium carbide epitaxial thin films. Chem. Mater. 2014, 26, 2374. [Google Scholar] [CrossRef]
  39. Sun, W.; Shah, S.A.; Chen, Y.; Tan, Z.; Gao, H.; Habib, T.; Radovic, M.; Green, M.J. Electrochemical etching of Ti2AlC to Ti2CTX (MXene) in low-concentration hydrochloric acid solution. J. Mater. Chem. A 2017, 5, 21663–21668. [Google Scholar] [CrossRef]
  40. Li, T.; Yao, L.; Liu, Q.; Gu, J.; Luo, R.; Li, J.; Yan, X.; Wang, W.; Liu, P.; Chen, B.; et al. Fluorine-free synthesis of high-purity Ti3C2Tx (T=OH, O) via alkali treatment. Angew. Chem. Int. Ed. 2018, 57, 6115–6119. [Google Scholar] [CrossRef]
  41. Li, M.; Lu, J.; Luo, K.; Li, Y.; Chang, K.; Chen, K.; Zhou, J.; Rosen, J.; Hultman, L.; Eklund, P.; et al. Element replacement approach by reaction with Lewis acidic molten salts to synthesize nanolaminated MAX phases and MXenes. J. Am. Chem. Soc. 2019, 141, 4730–4737. [Google Scholar] [CrossRef] [PubMed]
  42. Jawaid, A.; Hassan, A.; Neher, G.; Nepal, D.; Pachter, R.; Kennedy, W.J.; Ramakrishnan, S.; Vaia, R.A. Halogen etch of Ti3AlC2 MAX phase for MXene fabrication. ACS Nano 2021, 15, 2771–2777. [Google Scholar] [CrossRef] [PubMed]
  43. Xu, C.; Wang, L.; Liu, Z.; Chen, L.; Guo, J.; Kang, N.; Ma, X.-L.; Cheng, H.M.; Ren, W. Large-area high-quality 2D ultrathin Mo2C superconducting crystals. Nat. Mater. 2015, 14, 1135–1141. [Google Scholar] [CrossRef] [PubMed]
  44. Zhang, F.; Zhang, Z.; Wang, H.; Chan, C.H.; Chan, N.Y.; Chen, X.X.; Dai, J.-Y. Plasma-enhanced pulsed-laser deposition of single-crystalline Mo2C ultrathin superconducting films. Phys. Rev. Mater. 2017, 1, 34002. [Google Scholar] [CrossRef]
  45. Xiao, X.; Yu, H.; Jin, H.; Wu, M.; Fang, Y.; Sun, J.; Hu, Z.; Li, T.; Wu, J.; Huang, L.; et al. Salt-templated synthesis of 2D metallic MoN and other nitrides. ACS Nano 2017, 11, 2180–2186. [Google Scholar] [CrossRef]
  46. Wang, J.; Liu, S.; Wang, Y.; Wang, T.; Shang, S.; Ren, W. Magnetron-sputtering deposited molybdenum carbide MXene thin films as a saturable absorber for passively Q-switched lasers. J. Mater. Chem. C 2020, 8, 1608–1613. [Google Scholar] [CrossRef]
  47. Gürbüz, B.; Ciftci, F. Bio-electric-electronics and tissue engineering applications of MXenes wearable materials: A review. Chem. Eng. J. 2024, 489, 151230. [Google Scholar] [CrossRef]
  48. Gul, I.; Sayed, M.; Saeed, T.; Rehman, F.; Naeem, A.; Gul, S.; Khan, Q.; Naz, K.; Rehman, M. Unveiling cutting-edge progress in the fundamentals of MXene: Synthesis strategies, energy and bio-environmental applications. Coord. Chem. Rev. 2024, 511, 215870. [Google Scholar] [CrossRef]
  49. Thakur, A.; Chandran, B.S.N.; Davidson, K.; Bedford, A.; Fang, H.; Im, Y.; Kanduri, V.; Wyatt, B.C.; Nemani, S.K.; Poliukhova, V.; et al. Step-by-step guide for synthesis and delamination of Ti3C2Tx MXene. Small Methods 2023, 7, 2300030. [Google Scholar] [CrossRef]
  50. Pakchin, P.S.; Nakhjavani, S.A.; Saber, R.; Ghanbari, H.; Omidi, Y. Recent advances in simultaneous electrochemical multi-analyte sensing platforms. TrAC Trends Anal. Chem. 2017, 92, 32–41. [Google Scholar] [CrossRef]
  51. Ma, Z.; Liu, N. Design of immunoprobes for electrochemical multiplexed tumor marker detection. Expert Rev. Mol. Diag. 2015, 15, 1075–1083. [Google Scholar] [CrossRef] [PubMed]
  52. Zupančič, U.; Rainbow, J.; Flynn, C.; Aidoo-Brown, J.; Estrela, P.; Moschou, D. Strategies for multiplexed electrochemical sensor development. In Modern Techniques in Biosensors. Studies in Systems, Decision and Control; Dutta, G., Biswas, A., Chakrabarti, A., Eds.; Springer: Singapore, 2021; Volume 327, pp. 63–93. [Google Scholar]
  53. Noviana, E.; Henry, C.S. Simultaneous electrochemical detection in paper-based analytical devices. Curr. Opin. Electrochem. 2020, 23, 1–6. [Google Scholar] [CrossRef]
  54. Feng, S.; Yu, L.; Yan, M.; Ye, J.; Huang, J.; Yang, X. Holey nitrogen-doped graphene aerogel for simultaneously electrochemical determination of ascorbic acid, dopamine and uric acid. Talanta 2021, 224, 121851. [Google Scholar] [CrossRef] [PubMed]
  55. Nantaphol, S.; Kava, A.A.; Channon, R.B.; Kondo, T.; Siangproh, W.; Chailapakul, O.; Henry, C.S. Janus electrochemistry: Simultaneous electrochemical detection at multiple working conditions in a paper-based analytical device. Anal. Chim. Acta 2019, 1056, 88–95. [Google Scholar] [CrossRef]
  56. Chikkaveeraiah, B.V.; Bhirde, A.A.; Morgan, N.Y.; Eden, H.S.; Chen, X. Electrochemical immunosensors for detection of cancer protein biomarkers. ACS Nano 2012, 6, 6546–6561. [Google Scholar] [CrossRef]
  57. Karimzadeh, Z.; Hasanzadeh, M.; Isildak, I.; Khalilzadeh, B. Multiplex bioassaying of cancer proteins and biomacromolecules: Nanotechnological, structural and technical perspectives. Int. J. Biol. Macromol. 2020, 165, 3020–3039. [Google Scholar] [CrossRef]
  58. Grabowska, I.; Zapotoczny, S.; Chlopicki, S. Multiplex electrochemical aptasensors for detection of endothelial dysfunction: Ready for prime time? TrAC Trends Anal. Chem. 2023, 169, 117372. [Google Scholar] [CrossRef]
  59. Feng, J.; Chu, C.; Ma, Z. Electrochemical signal substance for multiplexed immunosensing interface construction: A mini review. Molecules 2022, 27, 267. [Google Scholar] [CrossRef]
  60. Popov, A.; Brasiunas, B.; Kausaite-Minkstimiene, A.; Ramanaviciene, A. Metal nanoparticle and quantum dot tags for signal amplification in electrochemical immunosensors for biomarker detection. Chemosensors 2021, 9, 85. [Google Scholar] [CrossRef]
  61. Kondzior, M.; Grabowska, I. Antibody-electroactive probe conjugates based electrochemical immunosensors. Sensors 2020, 20, 2014. [Google Scholar] [CrossRef]
  62. Filik, H.; Avan, A.A. Nanostructures for nonlabeled and labeled electrochemical immunosensors: Simultaneous electrochemical detection of cancer markers: A review. Talanta 2019, 205, 120153. [Google Scholar] [CrossRef] [PubMed]
  63. Tabrizi, M.A.; Shamsipur, M.; Saber, R.; Sarkar, S. Simultaneous determination of CYC and VEGF165 tumor markers based on immobilization of flavin adenine dinucleotide and thionine as probes on reduced graphene oxide-poly(amidoamine)/gold nanocomposite modified dual working screen-printed electrode. Sens. Actuators B Chem. 2017, 240, 1174–1181. [Google Scholar] [CrossRef]
  64. Wardani, N.I.; Kanatharana, P.; Thavarungkul, P.; Limbut, W. Molecularly imprinted polymer dual electrochemical sensor for the one-step determination of albuminuria to creatinine ratio (ACR). Talanta 2023, 265, 124769. [Google Scholar] [CrossRef] [PubMed]
  65. Hui, X.; Sharifuzzaman, M.; Sharma, S.; Xuan, X.; Zhang, S.; Ko, S.G.; Yoon, S.H.; Park, J.Y. High-performance flexible electrochemical heavy metal sensor based on layer-by-layer assembly of Ti3C2Tx/MWNTs nanocomposites for noninvasive detection of copper and zinc ions in human biofluids. ACS Appl. Mater. Interfaces 2020, 12, 48928–48937. [Google Scholar] [CrossRef]
  66. Murugan, N.; Jerome, R.; Preethika, M.; Sundaramurthy, A.; Sundramoorthy, A.K. 2D-titanium carbide (MXene) based selective electrochemical sensor for simultaneous detection of ascorbic acid, dopamine and uric acid. J. Mater. Sci. Technol. 2021, 72, 122–131. [Google Scholar] [CrossRef]
  67. Wang, Y.; Zhao, P.; Gao, B.; Yuan, M.; Yu, J.; Wang, Z.; Chen, X. Self-reduction of bimetallic nanoparticles on flexible MXene-graphene electrodes for simultaneous detection of ascorbic acid, dopamine, and uric acid. Microchem. J. 2023, 185, 108177. [Google Scholar] [CrossRef]
  68. Jia, D.; Yang, T.; Wang, K.; Zhou, L.; Wang, E.; Chou, K.-C.; Wang, H.; Hou, X. Facile in-situ synthesis of Ti3C2Tx/TiO2 nanowires toward simultaneous determination of ascorbic acid, dopamine and uric acid. J. Alloys Compd. 2024, 985, 173392. [Google Scholar] [CrossRef]
  69. Zhu, Y.; Tian, Q.; Li, X.; Wu, L.; Yu, A.; Lai, G.; Fu, L.; Wei, Q.; Dai, D.; Jiang, N.; et al. A double-deck structure of reduced graphene oxide modified porous Ti3C2Tx electrode towards ultrasensitive and simultaneous detection of dopamine and uric acid. Biosensors 2021, 11, 462. [Google Scholar] [CrossRef]
  70. Shang, L.; Li, R.; Li, H.; Yu, S.; Sun, X.; Yu, Y.; Ren, Q. The simultaneous detection of dopamine and uric acid in vivo based on a 3D reduced graphene oxide–MXene composite electrode. Molecules 2024, 29, 1936. [Google Scholar] [CrossRef]
  71. Mun, T.J.; Yang, E.; Moon, J.; Kim, S.; Park, S.G.; Kim, M.; Choi, N.; Lee, Y.; Kim, S.J.; Seong, H. Silane-functionalized MXene-PEGDA hydrogel for enhanced electrochemical sensing of neurotransmitters and antioxidants. ACS Appl. Polym. Mater. 2024, 6, 9533–9544. [Google Scholar] [CrossRef]
  72. Elumalai, S.; Mani, V.; Jeromiyas, N.; Ponnusamy, V.K.; Yoshimura, M. A composite film prepared from titanium carbide Ti3C2Tx (MXene) and gold nanoparticles for voltammetric determination of uric acid and folic acid. Microchim. Acta 2020, 187, 33. [Google Scholar] [CrossRef] [PubMed]
  73. Avan, A.A.; Filik, H. Synthesis and characteristics of Cu/N-codoped Ti3C2Tx MXene using copper-aniline solid complex and application to simultaneous electrochemical sensing of adenine and guanine in artificial sweat. Anal. Lett. 2024, 57, 2972–2993. [Google Scholar] [CrossRef]
  74. Liu, J.; Jiang, X.T.; Zhang, R.Y.; Zhang, Y.; Wu, L.M.; Lu, W.; Li, J.Q.; Li, Y.C.; Zhang, H. MXene-enabled electrochemical microfluidic biosensor: Applications toward multicomponent continuous monitoring in whole blood. Adv. Funct. Mater. 2019, 29, 1807326. [Google Scholar] [CrossRef]
  75. Ji, G.; Wang, J.; Wang, Z.; Zhang, S.; Fang, Z.; Wang, Y.; Gao, Z. Transient paper-based electrochemical biosensor fabricated by superadditive Cu-TCPP(Fe)/MXene for multipathway non-invasive, highly sensitive detection of bodily metabolites. Biosens. Bioelectron. 2024, 261, 116509. [Google Scholar] [CrossRef]
  76. Lei, Y.; Zhao, W.; Zhang, Y.; Jiang, Q.; He, J.-H.; Baeumner, A.J.; Wolfbeis, O.S.; Wang, Z.L.; Salama, K.N.; Alshareef, H.N. A MXene-based wearable biosensor system for high-performance in vitro perspiration analysis. Small 2019, 15, 1901190. [Google Scholar] [CrossRef]
  77. Li, M.; Wang, L.; Liu, R.; Li, J.; Zhang, Q.; Shi, G.; Li, Y.; Hou, C.; Wang, H. A highly integrated sensing paper for wearable electrochemical sweat analysis. Biosens. Bioelectron. 2021, 174, 112828. [Google Scholar] [CrossRef]
  78. Sharifuzzaman, M.; Barman, S.C.; Zahed, M.A.; Sharma, S.; Yoon, H.; Nah, J.S.; Kim, H.; Park, J.Y. An electrodeposited MXene-Ti3C2Tx nanosheets functionalized by task-specific ionic liquid for simultaneous and multiplexed detection of bladder cancer biomarkers. Small 2020, 16, 2002517. [Google Scholar] [CrossRef]
  79. Zhang, W.; Du, J.; Wang, K.; Li, Y.; Chen, C.; Yang, L.; Kan, Z.; Dong, B.; Wang, L.; Xu, L. Integrated dual-channel electrochemical immunosensor for early diagnosis and monitoring of periodontitis by detecting multiple biomarkers in saliva. Anal. Chim. Acta 2023, 1247, 340878. [Google Scholar] [CrossRef]
  80. Reza, M.S.; Sharifuzzaman, M.; Asaduzzaman, M.; Islam, Z.; Lee, Y.; Kim, D.; Park, J.Y. Polyaromatic hydrocarbon-functionalized 2D MXene-based 3D porous antifouling nanocomposite with long shelf life for high-performance electrochemical immunosensor applications. ACS Appl. Mater. Interfaces 2024, 16, 31610–31623. [Google Scholar] [CrossRef]
  81. Liu, Y.; Zhang, Y.; Li, Z.; Li, Z.; Zhou, S.; Xia, Y.; Mou, L. Fast and in-situ electrodeposition of MXene/AuNPs composite for multiplexed and sensitive detection of infectious biomarkers using an electrochemical biosensor. Microchem. J. 2024, 207, 112064. [Google Scholar] [CrossRef]
  82. Mohammadniaei, M.; Koyappayil, A.; Sun, Y.; Min, J.; Lee, M.-H. Gold nanoparticle/MXene for multiple and sensitive detection of oncomiRs based on synergetic signal amplification. Biosens. Bioelectron. 2020, 159, 112208. [Google Scholar] [CrossRef] [PubMed]
  83. Zhao, J.; He, C.; Wu, W.; Yang, H.; Peng, L.; Wen, L.; Hu, Z.; Hou, C.; Huo, D. MXene-MoS2 carbon-fiber-based flexible electrochemical interface for multiple bioanalysis in biofluids. Chem. Eng. J. 2022, 446, 136841. [Google Scholar] [CrossRef]
  84. Kalasin, S.; Sangnuang, P. Multiplex wearable electrochemical sensors fabricated from sodiated polymers and Mxene nanosheet to measure sodium and creatinine levels in sweat. ACS Appl. Nano Mater. 2023, 6, 18209–18221. [Google Scholar] [CrossRef]
  85. Zhang, Y.; Sun, Y.; Han, J.; Zhang, M.; Li, F.; Yang, D. High-sensitivity flexible electrochemical sensor for real-time multi-analyte sweat analysis. Talanta 2025, 287, 127644. [Google Scholar] [CrossRef]
  86. Zhang, Y.; Jiang, X.; Zhang, J.; Zhang, H.; Li, Y. Simultaneous voltammetric determination of acetaminophen and isoniazid using MXene modified screen-printed electrode. Biosens. Bioelectron. 2019, 130, 315–321. [Google Scholar] [CrossRef]
  87. Mari, E.; Duraisamy, M.; Eswaran, M.; Sellappan, S.; Won, K.; Chandra, P.; Tsai, P.-C.; Huang, P.-C.; Chen, Y.-H.; Lin, Y.-C.; et al. Highly electrochemically active Ti3C2Tx MXene/MWCNT nanocomposite for the simultaneous sensing of paracetamol, theophylline, and caffeine in human blood samples. Microchim. Acta 2024, 191, 212. [Google Scholar] [CrossRef]
  88. Zhang, Y.; Fan, J.; Lu, Y.; Zhang, Y. ZIF-8 nanoparticles densely covered MXene as functionalized platform for electrochemical detection of medical small molecules. Electrochim. Acta 2024, 502, 144872. [Google Scholar] [CrossRef]
  89. Rajaji, U.; Ganesh, P.S.; Kim, S.Y.; Govindasamy, M.; Alshgari, R.A.; Liu, T.Y. MoS2 sphere/2D S-Ti3C2 MXene nanocatalysts on laser-induced graphene electrodes for hazardous aristolochic acid and roxarsone electrochemical detection. ACS Appl. Nano Mater. 2022, 5, 3252–3264. [Google Scholar] [CrossRef]
  90. Devi, R.K.; Ganesan, M.; Chen, T.-W.; Chen, S.-M.; Abbasi, A.M.; Ali, M.A.; Elshikh, M.S.; Yu, J.; Chuang, H.-Y.; Xu, B.; et al. MXene-interdigitated holey-graphene oxide nanocomposite for simultaneous detection of antibiotic and anticancer drugs with ultra-high sensitivity. Chem. Eng. J. 2023, 474, 145693–145706. [Google Scholar] [CrossRef]
  91. Ravipati, M.; Ramasamy, D.; Badhulika, S. Highly selective cobalt-MOF/vanadium carbide MXene hydrogel for simultaneous electrochemical determination of levothyroxine and carbamazepine in simulated blood serum. Electrochim. Acta 2025, 525, 146154. [Google Scholar] [CrossRef]
  92. Yin, H.; Truskewycz, A.; Cole, I.S. Quantum dot (QD)-based probes for multiplexed determination of heavy metal ions. Microchim. Acta 2020, 187, 336. [Google Scholar] [CrossRef] [PubMed]
  93. Nair, R.R.; An, J.M.; Kim, J.; Kim, D. Review: Recent progress in fluorescent molecular systems for the detection of disease-related biomarkers in biofluids. Coord. Chem. Rev. 2023, 494, 215336. [Google Scholar] [CrossRef]
  94. Mandal, S.; Li, Z.; Chatterjee, T.; Khanna, K.; Montoya, K.; Dai, L.; Petersen, C.; Li, L.; Tewari, M.; Johnson-Buck, A.; et al. Direct kinetic fingerprinting for high-accuracy single-molecule counting of diverse disease biomarkers. Acc. Chem. Res. 2021, 54, 388–402. [Google Scholar] [CrossRef] [PubMed]
  95. Yuan, Q.; Wu, S.; Ye, C.; Liu, X.; Gao, J.; Cui, N.; Guo, P.; Lai, G.; Wei, Q.; Yang, M.; et al. Sensitivity enhancement of potassium ion (K+) detection based on graphene field-effect transistors with surface plasma pretreatment. Sens. Actuators B Chem. 2019, 285, 333–340. [Google Scholar] [CrossRef]
  96. Xiao, F.; Wang, L.; Duan, H. Nanomaterial based electrochemical sensors for in vitro detection of small molecule metabolites. Biotechnol. Adv. 2016, 34, 234–249. [Google Scholar] [CrossRef]
  97. Sangubotla, R.; Kim, J. Recent trends in analytical approaches for detecting neurotransmitters in Alzheimer’s disease. Trends Anal. Chem. 2018, 105, 240–250. [Google Scholar] [CrossRef]
  98. Xu, T.-Q.; Zhang, Q.-L.; Zheng, J.-N.; Lv, Z.-Y.; Wei, J.; Wang, A.-J.; Feng, J.-J. Simultaneous determination of dopamine and uric acid in the presence of ascorbic acid using Pt nanoparticles supported on reduced graphene oxide. Electrochim. Acta 2014, 115, 109–115. [Google Scholar] [CrossRef]
  99. Liang, X.-H.; Yu, A.-X.; Bo, X.-J.; Du, D.-Y.; Su, Z.-M. Metal/covalent-organic frameworks-based electrochemical sensors for the detection of ascorbic acid, dopamine and uric acid. Coord. Chem. Rev. 2023, 497, 215427. [Google Scholar] [CrossRef]
  100. Hussain, S.; Zaidi, S.A.; Vikraman, D.; Kim, H.-S.; Jung, J. Facile preparation of molybdenum carbide (Mo2C) nanoparticles and its effective utilization in electrochemical sensing of folic acid via imprinting. Biosens. Bioelectron. 2019, 140, 111330. [Google Scholar] [CrossRef]
  101. Liu, Y.; Li, J.; Xiao, S.; Liu, Y.; Bai, M.; Gong, L.; Zhao, J.; Chen, D. Revolutionizing precision medicine: Exploring wearable sensors for therapeutic drug monitoring and personalized therapy. Biosensors 2023, 13, 726. [Google Scholar] [CrossRef]
  102. Kalambate, P.K.; Noiphung, J.; Rodthongkum, N.; Larpant, N.; Thirabowonkitphithan, P.; Rojanarata, T.; Hasan, M.; Huang, Y.; Laiwattanapaisal, W. Nanomaterials-based electrochemical sensors and biosensors for the detection of non-steroidal anti-inflammatory drugs. TrAC Trends Anal. Chem. 2021, 143, 116403. [Google Scholar] [CrossRef]
  103. Kumar, S.; Kumari, N.; Seo, Y. MXenes: Versatile 2D materials with tailored surface chemistry and diverse applications. J. Energy Chem. 2024, 90, 253–293. [Google Scholar] [CrossRef]
  104. Peng, M.; Dong, M.; Wei, W.; Xu, H.; Liu, C.; Shen, C. The introduction of amino termination on Ti3C2 MXene surface for its flexible film with excellent property. Carbon 2021, 179, 400–407. [Google Scholar] [CrossRef]
  105. Ye, C.; Lukas, H.; Wang, M.; Lee, Y.; Gao, W. Nucleic acid-based wearable and implantable electrochemical sensors. Chem. Soc. Rev. 2024, 53, 7960–7982. [Google Scholar] [CrossRef]
  106. Gao, Z.-W.; Yu, Y.; Chen, S.-H.; Li, Y.-Y.; Liu, Z.-H.; Yang, M.; Li, P.-H.; Song, Z.-Y.; Huang, X.-J. Machine learning-driven simultaneous quantification of Cd(II) and Cu(II) on Co2P/CoP heterostructure: Enhanced electrochemical signals via activated Co-P electron bridge. J. Hazard. Mater. 2025, 491, 138030. [Google Scholar] [CrossRef]
  107. Alagarsamy, K.N.; Saleth, L.R.; Diedkova, K.; Zahorodna, V.; Gogotsi, O.; Pogorielov, M.; Dhingra, S. MXenes in healthcare: Transformative applications and challenges in medical diagnostics and therapeutics. Nanoscale 2025, 17, 11785–11811. [Google Scholar] [CrossRef]
Figure 1. Schematic of the different molecular structures of MXene and the constituent elements of MAX and MXene. Reproduced with permission from [36]. * (blue) refers to the elements in blue color below (Sc, Ti, V, etc.), and * (red) refers to the elements in red color below (Al, Si, P, etc.).
Figure 1. Schematic of the different molecular structures of MXene and the constituent elements of MAX and MXene. Reproduced with permission from [36]. * (blue) refers to the elements in blue color below (Sc, Ti, V, etc.), and * (red) refers to the elements in red color below (Al, Si, P, etc.).
Ijms 26 05368 g001
Figure 2. Schematic diagram for simultaneous electrochemical detection.
Figure 2. Schematic diagram for simultaneous electrochemical detection.
Ijms 26 05368 g002
Figure 3. Fabrication process of flexible Ti3C2Tx/MWCNTs/Au electrode (a) and its working mechanism for Cu2+ and Zn2+ detection (b). Reproduced with permission from [65].
Figure 3. Fabrication process of flexible Ti3C2Tx/MWCNTs/Au electrode (a) and its working mechanism for Cu2+ and Zn2+ detection (b). Reproduced with permission from [65].
Ijms 26 05368 g003
Figure 4. (a) Schematic of 2D MXene structure (top left), 3D MXene composite hydrogel (bottom right), and SEM image of the 3D MXene composite hydrogel (bottom left, scale bar = 10 μm). Reproduced with permission from [71]. (b) Schematic of the fabrication of a MXene-based microfluidic chip for the simultaneous and continuous analysis of urea, UA, and Cre in whole blood. Reproduced with permission from [74]. (c) Schematic diagram of oxygen-enriched GOx(LOx)/CNTs/Ti3C2Tx/PB/CFM electrode. Reproduced with permission from [76]. (d) Structural diagram of the HIS paper. Reproduced with permission from [77].
Figure 4. (a) Schematic of 2D MXene structure (top left), 3D MXene composite hydrogel (bottom right), and SEM image of the 3D MXene composite hydrogel (bottom left, scale bar = 10 μm). Reproduced with permission from [71]. (b) Schematic of the fabrication of a MXene-based microfluidic chip for the simultaneous and continuous analysis of urea, UA, and Cre in whole blood. Reproduced with permission from [74]. (c) Schematic diagram of oxygen-enriched GOx(LOx)/CNTs/Ti3C2Tx/PB/CFM electrode. Reproduced with permission from [76]. (d) Structural diagram of the HIS paper. Reproduced with permission from [77].
Ijms 26 05368 g004
Figure 5. (a) Schematic of the preparation process of a 3D-MXting, antifouling nanocomposite. Reproduced with permission from [80]. (b) Schematic diagram of the assay procedure for simultaneous detection of microRNA-21 and microRNA-141. Reproduced with permission from [82].
Figure 5. (a) Schematic of the preparation process of a 3D-MXting, antifouling nanocomposite. Reproduced with permission from [80]. (b) Schematic diagram of the assay procedure for simultaneous detection of microRNA-21 and microRNA-141. Reproduced with permission from [82].
Ijms 26 05368 g005
Figure 6. (a) Mechanism to dope cationic ions via a carbon-PEG/PEDOT:PSS or PPy/Ti3C2Tx nanosheet. (b) Potentiometric sensing mechanism to detect Na+ in sweat interference. (c) Voltametric sensing mechanism to detect creatinine in sweat interference. Reproduced with permission from [84]. (d) Schematic of the preparation process of NS-TiO2@MXene-HG and NS-TiO2@MXene-HG/rGSPE. Reproduced with permission from [85].
Figure 6. (a) Mechanism to dope cationic ions via a carbon-PEG/PEDOT:PSS or PPy/Ti3C2Tx nanosheet. (b) Potentiometric sensing mechanism to detect Na+ in sweat interference. (c) Voltametric sensing mechanism to detect creatinine in sweat interference. Reproduced with permission from [84]. (d) Schematic of the preparation process of NS-TiO2@MXene-HG and NS-TiO2@MXene-HG/rGSPE. Reproduced with permission from [85].
Ijms 26 05368 g006
Figure 7. (a) Schematic of the preparation procedure of Ti3C2Tx@AuNPs-ZnO@NC. Reproduced with permission from [88]. (b) Illustration of the synthesis of p-TC/hGO nanocomposite and its application in NFT and NLT simultaneous electrochemical detection. Reproduced with permission from [90].
Figure 7. (a) Schematic of the preparation procedure of Ti3C2Tx@AuNPs-ZnO@NC. Reproduced with permission from [88]. (b) Illustration of the synthesis of p-TC/hGO nanocomposite and its application in NFT and NLT simultaneous electrochemical detection. Reproduced with permission from [90].
Ijms 26 05368 g007
Figure 8. Schematic of biofluids and corresponding targets detected by MXene-based, multiplexed electrochemical sensors.
Figure 8. Schematic of biofluids and corresponding targets detected by MXene-based, multiplexed electrochemical sensors.
Ijms 26 05368 g008
Table 1. A comparison of different strategies for simultaneous electrochemical detection.
Table 1. A comparison of different strategies for simultaneous electrochemical detection.
StrategyAdvantagesDisadvantages
Electrode modification
(1)
Improves sensitivity and reduces detection limits.
(2)
Directly distinguishes between targets with similar potentials by altering reaction kinetics.
(3)
Requires only a single electrode (simple setup).
(1)
Limited to electrochemically active analytes.
(2)
Some materials (e.g., noble metals) are expensive and increase the cost.
Multi-electrode
(1)
High robustness and accuracy.
(2)
Suitable for both electroactive and non-electroactive analytes.
(1)
High cost.
(2)
Requires multi-channel electrochemical analyzers.
(3)
Fabrication complexity for electrode arrays.
Multi-label
(1)
Low cost.
(2)
Requires only a single electrode.
(3)
Versatile labels (enzymes, nanoparticles, redox molecules, etc.) and flexible design.
(1)
Limited to non-electroactive targets.
(2)
Require tedious modification steps.
(3)
Signal interference (cross-reactivity).
Table 2. Summary of MXene-based electrochemical sensors for multiplexed detection in biofluids.
Table 2. Summary of MXene-based electrochemical sensors for multiplexed detection in biofluids.
Working Electrodes [Ref.]Signal Separation StrategiesAnalytesBiofluids *Analytical MethodsSensitivityLimit of DetectionLinear Range
Ti3C2Tx/MWCNTs/Au [65]/Cu2+
Zn2+
Urine and sweatSWASV/Cu2+: 0.1 ppb
Zn2+: 1.5 ppb
Cu2+: 10–600 ppb
Zn2+: 350–830 ppb
Ti-C-Tx/GCE [66]Electrode modificationDA
UA
AA
UrineDPV/AA: 4.64 μM
DA: 0.06 μM
UA: 0.075 μM
AA: 100–1000 μM
DA: 0.5–50 μM
UA: 0.5–4 μM & 100–1500 μM
Au-Pd/Ti3C2Tx/LSG [67]Electrode modificationAA
DA
UA
Urine and sweatDPV/AA: 3 μM
DA: 0.13 μM
UA: 1.47 μM
AA: 10–1600 μM
DA: 12–240 μM
UA: 8–100 μM & 200–800 μM
Ti3C2Tx/TiO2 NWs/GCE [68]Electrode modificationAA
DA
UA
UrineDPV/AA: 6.61 μM
DA: 0.093 μM
UA: 0.038 μM
AA: 300–1800 μM
DA: 2–33 μM
UA: 2–33 μM
Ti3C2Tx/rGO/GCE [69]Electrode modificationDA
UA
SerumDPV/DA: 9.5 nM
UA: 0.3 μM
DA: 0.1–100 μM
UA: 1–1000 μM
3D rGO-Ti3C2Tx/Cu wire [70]Electrode modificationDA
UA
FBS+rat striatumDPVDA: 0.74 µA/µM·cm2
UA: 2.96 µA/µM·cm2; 0.81 µA/µM·cm2
DA: 0.061 μM
UA: 0.085 μM
DA: 0.5–500 μM
UA: 0.5–60 μM; 80–450 μM
Ti3C2Tx-PEGDA hydrogel/Au [71]Electrode modificationDA
5-HT
UA
SerumDPV/DA: 2.55 μM
5-HT: 0.83 μM
UA: 25.11 μM
DA: 2.5–200 μM
5-HT: 1–100 μM
UA: 10–100 μM
AuNP@Ti3C2Tx/GCE [72]Electrode modificationUA
FA
SerumAmperometry
(i–t)
UA: 0.530 µA/µM·cm2
FA: 0.494 µA/µM·cm2
UA: 11.5 nM
FA: 6.20 nM
UA: 0.03–1520 μM
FA: 0.02–3580 μM
Cu@N-Ti3C2Tx/GCE [73]/Adenine
Guanine
Artificial sweatDPV/adenine: 0.01 μM
guanine: 0.02 μM
0.1–10 μM
Urease-MB/Ti3C2Tx/SPE for Urea and UA; Ti3C2Tx/SPE for Cre [74]Electrode modification and multi-electrodeUrea
UA
Cre
Whole bloodSWV/Urea: 0.02 mM
UA: 5 μM
Cre: 1.2 μM
Urea: 0.1–3 mM
UA: 30–500 μM
Cre: 10–400 μM
GOx(UOx)/Cu-TCPP(Fe)/Ti3C2Tx/paper-based electrode [75]Multi-electrodeGlu
UA
Artificial sweat, urine, and salivaCV/Glu: 1.88 aM
UA: 5.80 pM
Glu: 0.001 nM–5 mM
UA: 0.025 nM–5 mM
GOx(LOx)/CNTs/Ti3C2Tx/PB/CFMs [76]Multi-electrodeGlu
Lac
SweatCAGlu: 35.3 µA/mM·cm2
Lac: 11.4 µA/mM·cm2
Glu: 0.33 μM
Lac: 0.67 μM
Glu: 10–1500 μM
Lac: 0–22 mM
GOX(LOX)/MB/Ti3C2Tx/SPCE [77]Multi-electrodeGlu
Lac
SweatCA & DPVGlu: 2.4 nA/μM
Lac: 0.49 μA/mM
Glu: 17.05 μM
Lac: 3.73 μM
Glu: 0.08–1.25 mM
Lac: 0.3–20.3 mM
DIDμEs/MXNSs-AFBPB [78]Multi-electrodeApo-A1
NMP 22
Urine
DPV
/Apo-A1: 0.3 pg/mL
NMP 22: 0.7 pg/mL
0.1 pg/mL–50 ng/mL
IrOx/Ti3C2Tx/SPE [79]Multi-electrodeIL-1β
MMP-8
Artificial saliva and clinicopathological salivaDPV/IL-1β: 0.014 ng/mL
MMP-8: 0.13 ng/ mL
IL-1β: 0.1–100 ng/mL
MMP-8: 1–200 ng/mL
3D-MXting/Au [80]Multi-electrodeCRP
Ferritin
SerumCV/CRP: 6.2 pg/mL
Ferritin: 4.2 pg/mL
0.01–100 ng/mL
AuNPs and Ti3C2Tx-SPE [81]Multi-electrodeHBsAg
Anti-HIV
Anti-TP
SerumDPV/HBsAg: 0.01 ng/mL
Anti-HIV: 0.10 ng/mL
Anti-TP: 0.11 ng/mL
HBsAg: 0.05–1000 ng/mL
Anti-HIV: 0.25–100 ng/mL
Anti-TP: 0.35–140 ng/mL
AuNP@Ti3C2Tx/SPGE [82]Multi-electrode and multi-labelMicroRNA-21
MicroRNA-141
PlasmaDPV/microRNA-21: 204 aM
microRNA-141: 138 aM
500 aM–50 nM
CFP-Ti3C2Tx-MoS2 for AA, DA and UA; CFP-Ti3C2Tx-MoS2-AuNPs for microRNA [83]Electrode modification and multi-electrodeAA
DA
UA
MicroRNA
Urine (AA, DA, UA) and serum (microRNA)DPV/AA: 0.89 μM
DA: 0.23 μM
UA: 0.35 μM
MicroRNA: 3.16 aM
AA: 10–1000 μM
DA: 0.5–200 μM
UA: 0.5–150 μM
MicroRNA: 0.1 fM–10 fM; 10 fM to 10 nM
TE/carbon-PEG/PEDOT:PSS/Ti3C2Tx/ISM/MIL for Na+; TE/carbon-PEG/PPy/Ti3C2Tx/SM/MIL for Cre [84]Multi-electrodeNa+
Cre
SweatPotentiometry
DPV
Na+: –58.9 mV/dec
Cre: 0.014 ± 0.001 μA/μM
Na+: 10–6.2 M
Cre: 0.12 μM
Na+: 10–6–10–1 M
Cre: 0.6–2800 μM
NS-TiO2@MXene-HG/rGSPE for AA, DA and UA; ISM/rGSPE for K+ [85]Electrode modification and multi-electrodeAA
DA
UA
K+
Sweati–t
OCPT
AA: 20.78 µA/µM·cm2
DA: 32.78 µA/µM·cm2
/
/
AA: 0.025 μM
DA: 0.1 μM
UA: 0.14 μM
/
AA: 0.1–2200 μM
DA: 0.25–100 μM; 100–400 μM
UA: 0.25–100 μM; 100–225 μM
K+: 0.19–24 mM; 24–125 mM
Ti3C2Tx/SPE [86]/ACOP
INZ
SerumDPV/ACOP: 0.048 μM
INZ: 0.064 mM
ACOP: 0.25–2000 μM
INZ: 0.1–4.6 mM
Ti3C2Tx-MWCNT/SPE [87]Electrode modificationPA
TP
CF
SerumDPVPA: 2.194 µA/µM·cm2
TP: 2.179 µA/µM·cm2
CF: 5.035 µA/µM·cm2
PA: 0.23 µM
TP: 0.57 µM
CF: 0.43 µM
PA: 1.0–90.1 µM
TP: 2.0–62.0 µM
CF: 2.0–90.9 µM
Ti3C2Tx@AuNPs-ZnO@NC/GCE [88]/DA
ACOP
XA
BloodDPV/DA: 0.041 μM
AC: 0.059 μM
XA: 0.067 μM
DA: 3–200 μM
AC: 15–500 μM
XA: 8–350 μM
MoS2/S-Ti3C2/LGE [89]/AA’
ROX
Urine and serumDPVAA’: 69.955 µA/µM·cm2; 32.488 µA/µM·cm2
ROX: 56.972 µA/µM·cm2; 19.688 µA/µM·cm2
AA’: 1.65 nM
ROX: 2.31 nM
0.01–875.01 μM
p-TC/hGO/GCE [90]Electrode modificationNFT
NLT
Artificial urineDPVNFT: 52.8 µA/µM·cm2
NLT: 19.5 µA/µM·cm2
NFT: 1.2 nM
NLT: 1.9 nM
NFT: 0.05–135 μM
NLT: 0.05–158 μM
MOF-71/V2C MXene–hydrogel [91]/LT4
CBZ
Simulated serumDPV/LT4: 5.6 nM
CBZ: 6.7 nM
LT4: 10 nM–100 μM
CBZ: 10 nM–500 μM
Abbreviation: MWCNTs: multiwalled carbon nanotubes; GCE: glassy carbon electrode; DA: dopamine; UA: uric acid; AA: ascorbic acid; LSG: laser-scribed graphene; TiO2 NWs: TiO2 nanowires; rGO: reduced graphene oxide; FBS: fetal bovine serum; PEGDA: poly(ethylene glycol) diacrylate; 5-HT: 5-hydroxytryptamine; FA: folic acid; Cu@N-Ti3C2Tx: copper and nitrogen co-doped Ti3C2Tx; MB: methylene blue; SPE: screen-printed electrode; Cre: creatinine; GOx: glucose oxidase; UOx: uric acid oxidase; Glu: glucose; LOx: lactate oxidase; PB: Prussian blue; CFMs: carbon fiber membranes; Lac: lactate; SPCE: screen-printed carbon electrode; DIDμEs: dual interdigitated microelectrodes; MXNSs: Ti3C2Tx-MXene nanosheets; AFBPB: 4-amino-1-(4-formyl-benzyl) pyridinium bromide; IL-1β: interleukin-1β; MMP-8: matrix metalloproteinase-8; 3D-MXting: BSA/Al-Ti3C2Tx@1-pyrenebutyric acid/glutaraldehyde; CRP: C-reactive protein; SPGE: screen-printed gold electrodes; CFP: carbon fiber paper; TE: textile electrode; PEG: polyethylene glycol; PEDOT:PSS: poly(3,4-ethylenedioxythiophene) polystyrenesulfonate; ISM: ion-selective membrane; MIL: minimizing-interference layer; PPy: polypyrrole; SM: sensing material; NS-TiO2@MXene-HG: nitrogen and sulfur co-doped holey graphene and MXene, with in situ-grown TiO2 nanoparticles on the MXene; rGSPE: reduced graphene oxide-modified screen-printed electrode; OCPT: open circuit potential test; ACOP: acetaminophen; INZ: isoniazid; PA: paracetamol (acetaminophen); TP: theophylline; CF: caffeine; NC: N-doped carbon; LGE: laser-induced graphene electrode; XA: xanthine; AA’: aristolochic acid; ROX: roxarsone; p-TC/hGO: nanocomposite of holey graphene oxide with partially oxidized titanium carbide; NFT: nitrofurantoin; NLT: nilutamide; MOF: metal–organic framework; LT4: levothyroxine; CBZ: carbamazepine. *: Unless otherwise noted, biofluids in the table refer to those from humans.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yang, M.; Xie, C.; Lu, H. Advances in MXene-Based Electrochemical Sensors for Multiplexed Detection in Biofluids. Int. J. Mol. Sci. 2025, 26, 5368. https://doi.org/10.3390/ijms26115368

AMA Style

Yang M, Xie C, Lu H. Advances in MXene-Based Electrochemical Sensors for Multiplexed Detection in Biofluids. International Journal of Molecular Sciences. 2025; 26(11):5368. https://doi.org/10.3390/ijms26115368

Chicago/Turabian Style

Yang, Meiqing, Congkai Xie, and Haozi Lu. 2025. "Advances in MXene-Based Electrochemical Sensors for Multiplexed Detection in Biofluids" International Journal of Molecular Sciences 26, no. 11: 5368. https://doi.org/10.3390/ijms26115368

APA Style

Yang, M., Xie, C., & Lu, H. (2025). Advances in MXene-Based Electrochemical Sensors for Multiplexed Detection in Biofluids. International Journal of Molecular Sciences, 26(11), 5368. https://doi.org/10.3390/ijms26115368

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop