Probe Molecules Research Articles

Reactivity-based detection of nitrite ion: Rapid colorimetric and fluorometric response down to nM level

Recent developments in our lab provided significant insight into the structure–reactivity relationship between electronic properties and the detection of nitrite ions. By fine-tuning electron-withdrawing and electron-donating power, the sulfonamide group on aniline moiety was found to be the fastest nitrite probe among the first generation of probe molecules. Based on our understanding of the detection mechanism, our attention was moved to additional modification by installing stronger electron-donating groups on the azo-coupling partner. Accordingly, the bis methoxy group version of the probe molecule was prepared. It showed clean conversion from the probe to the benzo[c]cinnoline product and excellent linear response to very low levels of nitrite ions. Proton NMR and high-resolution mass spectrometer captured the reaction between the probe molecule and nitrite ions. As the reaction with nitrite ion triggers diazonium intermediate formation followed by intramolecular cyclization, both absorption and emission property changes were monitored as the signal readout to assay nitrite ion. In this report, our design principle of a probe molecule and its performance in colorimetric and fluorimetric responses will be discussed. In addition, the low detection limit achieved by leveraging chromatographic separation and assaying by the mass detector will be discussed.

Influence of theoretical and semi-empirical peak models on the efficiency calculation in chiral chromatography

Height equivalent to theoretical plate (H) equations, such as the van Deemter or Knox-Saleem equations, and other efficiency vs. linear velocity equations (u), provide kinetic insights into chromatographic separations phenomena and column performance. In enantioselective separations, the peak shape of the two enantiomers can differ significantly and are often asymmetric. The peak efficiency calculations heavily impact these efficiency-flow profiles, leading to erroneous estimations of eddy diffusion, longitudinal diffusion, and mass transfer terms. In this work, new asymmetric peak functions are employed for modeling enantiomer peaks based on the Haarhoff-Van der Linde function, its generalized variant (GHVL), once Generalized Asymmetric Gaussian (AGN), and Twice Generalized Gaussian (TGN). The new models (AGN, TGN, and GHVL) incorporate higher statistical moments besides the zeroth, first, and second moments to account for two-sided asymmetry (fronting or tailing). The fit results are compared with the traditional efficiency calculation methods endorsed by official pharmacopeia and numerical estimation of moments from the raw data. Enantiomeric separations of ibuprofen and dl-homophenylalanine were chosen as probe molecules. The results demonstrate that non-linear least squares fitted functions provide better estimations of peak efficiency data even in the presence of high noise. In particular, the generalized models consistently offered the best quality fits for various peak shapes in chiral separations. Conversely, the half-height Gaussian method greatly overpredicted skewed peak efficiencies. This investigation reveals that the commonly held assumptions of peak shape and numerical integration of raw data are highly insufficient for chiral chromatography. The impact of asymmetry on plate height should not be overlooked when accurate data from efficiency-flow rate curves is derived. We advocate for the broader adoption of these new generalized peak (AGN, TGN, GHVL) models because they provide robustness at various SNRs that account for right or left asymmetry while accurately representing peak geometry.

Tailoring Rhodamine Probes: Oxyethylene Chains, Conjugation, and End Substituents in the Quest for Superior Hg2+ Sensing

AbstractThis study explores the impact of incorporating oxyethylene (OE) chains into rhodamine‐based dye molecules for the enhancement of photophysical properties in the context of chemical sensing. The introduction of OE chains provides several advantages, including improved water solubility, photostability and resistance to self‐assembled nanoaggregates formation. Despite these, the compound with oxyethylene chains showed poor response (~2‐fold) towards Hg2+ ions than that of dimeric probe (~20 fold) with no such substituents. Notably, dimeric compound shows a remarkable three‐fold larger response to Hg2+ ion compared to monomeric compound. This intriguing outcome is attributed to the extended conjugation within the dimeric structure, which can induce conformational change of the overall molecule. Moreover, the study investigates the effects of end substituents, such as electron‐donating (−OMe, improved response) and electron‐withdrawing (−NO2, poor response) groups, on the interaction with Hg2+ ions. The excellent sensitivity of the probe molecules is also evident in significantly low detection limits for Hg2+ ion (5–8 ppb) in real‐life water samples. The high recovery values (>95 %) with sufficient low standard deviation (<5%) indicates that quantitative analysis of Hg2+ is achievable using the current protocol. Beyond that, we have employed the probe 1 for intracellular (HEK293T cells) fluorescence imaging of Hg2+.

Exploring Aromatic Cage Flexibility Using Cosolvent Molecular Dynamics Simulations─An In-Silico Case Study of Tudor Domains.

Cosolvent molecular dynamics (MD) simulations have proven to be powerful in silico tools to predict hotspots for binding regions on protein surfaces. In the current study, the method was adapted and applied to two Tudor domain-containing proteins, namely Spindlin1 (SPIN1) and survival motor neuron protein (SMN). Tudor domains are characterized by so-called aromatic cages that recognize methylated lysine residues of protein targets. In the study, the conformational transitions from closed to open aromatic cage conformations were investigated by performing MD simulations with cosolvents using six different probe molecules. It is shown that a trajectory clustering approach in combination with volume and atomic distance tracking allows a reasonable discrimination between open and closed aromatic cage conformations and the docking of inhibitors yields very good reproducibility with crystal structures. Cosolvent MDs are suitable to capture the flexibility of aromatic cages and thus represent a promising tool for the optimization of inhibitors.

The Intramolecular Charge Transfer Mechanism by Which Chiral Self-Assembled H8-BINOL Vesicles Enantioselectively Recognize Amino Alcohols.

The chiral H8-BINOL derivatives R-1 and R-2 were efficiently synthesized via a Suzuki coupling reaction, and they can be used as novel dialdehyde fluorescent probes for the enantioselective recognition of R/S-2-amino-1-phenylethanol. In addition, R-1 is much more effective than R-2. Scanning electron microscope images and X-ray analyses show that R-1 can form supramolecular vesicles through the self-assembly effect of the π-π force and strong hydrogen bonding. As determined via analysis, the fluorescence of the probe was significantly enhanced by mixing a small amount of S-2-amino-1-phenylethanol into R-1, with a redshift of 38 nm, whereas no significant fluorescence response was observed in R-2-amino-1-phenylethanol. The enantioselective identification of S-2-amino-1-phenylethanol by the probe R-1 was further investigated through nuclear magnetic titration and fluorescence kinetic experiments and DFT calculations. The results showed that this mechanism was not only a simple reactive probe but also realized object recognition through an ICT mechanism. As the intramolecular hydrogen bond activated the carbonyl group on the probe R-1, the carbonyl carbon atom became positively charged. As a strong nucleophile, the amino group of S-2-amino-1-phenylethanol first transferred the amino electrons to a carbonyl carbocation, resulting in a significantly enhanced fluorescence of the probe R-1 and a 38 nm redshift. Similarly, S-2-amino-1-phenylethanol alone caused severe damage to the self-assembled vesicle structure of the probe molecule itself due to its spatial structure, which made R-1 highly enantioselective towards it.

Photocatalytic Deposition of Au Nanoparticles on Ti3C2Tx MXene Substrates for Surface-Enhanced Raman Scattering.

Surface-enhanced Raman scattering (SERS) is a promising technique for sensitive detection. The design and optimization of plasma-enhanced structures for SERS applications is an interesting challenge. In this study, we found that the SERS activity of MXene (Ti3C2Tx) can be improved by adding Au nanoparticles (NPs) in a simple photoreduction process. Fluoride-salt-etched MXene was deposited by drop-casting on a glass slide, and Au NPs were formed by the photocatalytic growth of gold(III) chloride trihydrate solutions under ultraviolet (UV) irradiation. The Au-MXene substrate formed by Au NPs anchored on the Ti3C2Tx sheet produced significant SERS through the synergistic effect of chemical and electromagnetic mechanisms. The structure and size of the Au-decorated MXene depended on the reaction time. When the MXene films were irradiated with a large number of UV photons, the size of the Au NPs increased. Hot spots were formed in the nanoscale gaps between the Au NPs, and the abundant surface functional groups of the MXene effectively adsorbed and interacted with the probe molecules. Simultaneously, as a SERS substrate, the proposed Au-MXene composite exhibited a wider linear range of 10-4-10-9 mol/L for detecting carbendazim. In addition, the enhancement factor of the optimized SERS substrate Au-MXene was 1.39 × 106, and its relative standard deviation was less than 13%. This study provides a new concept for extending experimental strategies to further improve the performance of SERS.

EM and CT synergistic SERS enhancement in Si/TiO2/Ag heterostructures via local interfacial effect

The Si/TiO2/Ag heterostructures with high SERS sensitivity were prepared by sol–gel and electrochemical self-assembly. The electromagnetic (EM) and charge transferring (CT) synergistic mechanism for SERS enhancement was explored by FDTD. The “localized interfacial effect (LIE)” of metal–semiconductor heterostructures can result in the CT between them and the charge carriers’ redistribution, which can facilitate the probe molecules’ adsorption and generate the 3D volume-enhancement of electromagnetic fields, therefore improve the SERS performance effectively. Furthermore, the morphology of Ag was flexibly regulated by changing the applied voltage, and the optimal SERS performance was achieved. With the R6G as a probe molecule, the ultra-low concentration of 10-13 M can be detected. The EF is estimated to be about 1.75 × 1011, and the RSD is about 4.3 %. The photocatalytic effect of Si/TiO2/Ag heterostructure can realize the SERS substrates’ UV self-cleaning and recyclable use with high stability.

Investigation of Aging Mechanism of Pt‐ZSM‐5 Catalysts for Non‐Oxidative Propane Dehydrogenation

AbstractA Pt‐ZSM5 catalyst, coked during propane dehydrogenation and regenerated with lean air, was studied by various in‐situ and ex‐situ methods. A newly developed isothermal ceramic flat‐bed reactor with inert surfaces is described and used in the experiments. Comparative measurements successfully demonstrated that temperature alone has no effect on the catalyst and that changes in conversion and selectivity are due to coke formation. Nuclear magnetic resonance (NMR) studies using triphenylphosphine probe molecules of activated and deactivated samples showed the localization of the Pt clusters inside and outside the zeolite pores. It was shown that the Pt clusters are mainly located inside the zeolites and that the mobilization of Pt by contact with oxygen leads to permanent aging.

Rigid symmetric Rhodamine fluorescent dyes as fast selective detection of aluminum and iron ions applied to cell imaging

Fluorescent probe molecules have the advantages of good selectivity, high sensitivity, and easy operation, which have attracted much attention. In this paper, a novel symmetric rhodamine fluorescent probe with structural rigidity was synthesized by a simple reaction using rhodamine 6G as raw material. And it was characterized by NMR and electrospray spray mass spectrometry. Single crystal was prepared by solvent evaporation method, which was the first single crystal of the compound reported domestically and internationally. Special spiral ring structures were observed inside the crystal. Among different competing cations, the probe exhibited high selectivity and good sensitivity towards Al3+ and Fe3+ metal ions. The limits of detection were 0.76 nM and 0.49 nM, respectively. In the presence of Al3+ and Fe3+, the solution changed from colorless to pink. At the same time, there was a significant shift in the UV–vis spectrum and fluorescence emission spectrum. The UV–vis absorption peak appeared at 530 nm, while the emission at 556 nm was turned on. In addition, biological experiments have shown that the RP probe has good membrane permeability and has the potential to detect Al3+ and Fe3+ in Hela cells.

A simple yet effective H2S‐activated fluorogenic probe for precise imaging of hepatitis and arthritis in situ

AbstractHepatitis and arthritis are prevalent inflammatory diseases, and the utilization of fluorogenic probes incorporating hydrogen sulfide (H2S) as a crucial mediator of inflammation presents significant opportunities for early detection. However, the poor in vivo biodistribution and limited targeted efficacy of molecule probes for inflammation imaging severely impede their ability to differentiate the extent of inflammation and provide real‐time monitoring of inflammatory levels. Therefore, we developed a highly efficient H2S‐activated near‐infrared (NIR) fluorogenic probe (hCy‐DNP) for real‐time tracking and capturing fluctuations in H2S levels within inflammatory lesions. hCy‐DNP demonstrates an exceptionally sensitive fluorescence response to H2S expression, enabling specific differentiation between various levels of lipopolysaccharide (LPS) ‐stimulated early hepatitis models in situ, while also facilitating visual monitoring for diagnosis and efficacy evaluation of arthritis. Therefore, hCy‐DNP offers an innovative tool for exploring early diagnosis and evaluating treatment effectiveness across diverse inflammatory diseases.

Optofluidic SERS based on Ag nanocubes with high sensitivity for detecting a prevalent water pollutant.

To enhance the integration and practical applicability of the Raman detection system, silver nanocubes (Ag NCs) were synthesized using a polyol method. A liquid-liquid interface approach was employed to transfer a monolayer of Ag NCs "film" onto a SiO2 substrate, resulting in the fabrication of a highly sensitive and uniform surface-enhanced Raman scattering (SERS) substrate denoted as "Ag NCs@SiO2." The electromagnetic field distribution of various dimers on the Ag NCs@SiO2 was analyzed using finite difference time domain (FDTD) software. The results reveal that the electromagnetic enhancement effect is most pronounced in cube-cube dimers, indicating that Ag NCs exhibit superior localized surface plasmon resonance (LSPR) response due to their well-defined geometric regularity and sharp geometric angles. For Rhodamine 6G (R6G) probe molecules, the Ag NCs@SiO2 shows ultrahigh sensitivity, with a limit of detection (LOD) of 10-12 mol/L, and the enhancement factor (EF) can reach 1.4 × 1010. The relative standard deviation (RSD) at the main characteristic peaks is below 10%, demonstrating good consistency in substrate performance. In addition, the Ag NCs@SiO2 modified with hexanethiol exhibits high sensitivity, uniformity, and repeatability in detecting for pyrene, with the LOD of 10-8 mol/L and a minimum RSD of 6.09% at the main characteristic peak, and effective recognition capabilities for pyrene and anthracene in mixed solutions. Finally, chemisorption and physisorption strategies were prepared in optofluidic channels and experimentally compared, enabling real-time detection of the pyrene solution. This method can achieve a rapid detection and precise differentiation of polycyclic aromatic hydrocarbons in a water pollutant.

On the Low-Pressure Hysteresis (LPH) in Gas Sorption Isotherms of Porous Carbons.

This study investigates the origin of low-pressure hysteresis (LPH) in the adsorption and desorption of three different probe molecules: carbon dioxide, nitrogen, and argon, across various adsorption temperatures (from cryogenic to room temperature), and within five different carbon materials: synthetic carbons (pristine and one post-synthetically oxidized) and natural coal. Significant attention is dedicated to elucidating LPH in oxidized samples outgassed at various temperatures (120-350°C). Experimental results show that insufficient outgassing temperature can lead to unreliable data due to artificial LPH and significantly underestimated textural properties, primarily caused by porosity blockage from substances like moisture. Conversely, in samples where heteroatoms have a stabilizing effect on texture, such as natural coal, careful consideration of outgassing temperature is crucial due to the risk of thermal degradation. Other factors contributing to LPH are adsorption temperature, and especially, kinetic limitations at cryogenic temperatures for cellulose-based carbons. Minor factors responsible for LPH are the physical state of the sample (monolith vs powder) and the flexibility of the porous system, both studied by carbon dioxide sorption. This study constitutes an important piece in the evaluation of LPH, providing practical recommendations and underlining the importance of experimental design, with implications for further research in this complex field.

A sandwich-structured multifunctional platform based on self-assembled Ti3C2Tx@Au NPs films, antibiotics, and silent region SERS probe for the capture, determination, and drug resistance analysis of Gram-positive bacteria.

A multifunctional surface-enhanced Raman scattering (SERS) platform integrating sensitive detection and drug resistance analysis was developed for Gram-positive bacteria. The substrate was based on self-assembled Ti3C2Tx@Au NPs films and capture molecule phytic acid (IP6) to achieve specific capture of Gram-positive bacteria and different bacteria were analyzed by fingerprint signal. It had advantages of good stability and homogeneity (RSD = 8.88%). The detection limit (LOD) was 102CFU/mL for Staphylococcus aureus and 103CFU/mL for MRSA, respectively. A sandwich structure was formed on the capture substrate by signal labels prepared by antibiotics (penicillin G and vancomycin) and non-interference SERS probe molecules (4-mercaptobenzonitrile (2223cm-1) and 2-amino-4-cyanopyridine (2240cm-1)) to improve sensitivity. The LOD of Au NPs@4-MBN@PG to S. aureus and Au NPs@AMCP@Van to MRSA and S. aureus were all improved to 10 CFU/mL, with a wide dynamic linear range from 108 to 10CFU/mL (R2 ≥ 0.992). The SERS platform can analyze the drug resistance of drug-resistant bacteria. Au NPs@4-MBN@PG was added to the substrate and captured MRSA to compare the SERS spectra of 4-MBN. The intensity inhomogeneity of 4-MBN at the same concentrations of MRSA and the nonlinearity at the different concentrations of MRSA revealed that MRSA was resistant to PG. Finally, the SERS platform achieved the determination of MRSA in blood. Therefore, this SERS platform has great significance for the determination and analysis of Gram-positive bacteria.

Evaluating the ATR-SEIRAS performance of electrodeposited copper CO2 reduction catalysts using a flow-through spectroelectrochemical cell

The attenuated total reflection-surface-enhanced infrared absorption spectroscopy (SEIRAS) activity of electrodeposited Cu nanoparticles on indium tin oxide-modified Si internal reflection elements is reported. The solution in the cell is easily, and repeatedly, exchanged between a copper deposition bath and a solution containing 4-methoxypyridine through the use of a flow-through spectroelectrochemical cell. 4-methoxypyridine is a convenient SEIRAS probe molecule exhibiting potential-dependent adsorption/desorption on the copper surface. Successive amounts of copper are deposited and then evaluated for electrochemical SEIRAS activity without the need to expose the Cu surface to ambient conditions. It is found that copper deposition charge densities of approximately 60 mC cm−2 exhibit the largest amplitude and most symmetric IR absorption peaks of the investigated electrodeposition conditions. Scanning electron microscopy images of the different Cu charge density films are correlated with the SEIRAS results and establish that close-packed two-dimensional, percolated arrays of oblate, ellipsoidal Cu nanoparticles are responsible for ideal SEIRAS performance and three-dimensional aggregates of larger particles should be avoided. Textured films of Cu nanoparticles are used to determine the adsorbed species present on the copper surface during CO2 electroreduction at low overpotentials. Evidence of adsorbed CO and COH is found at lower overpotentials than those described in previous reports.

Anionic Effects on Concentrated Aqueous Lithium Ion Dynamics.

The dynamics, orientational anisotropy, diffusivity, viscosity, and density were measured for concentrated lithium salt solutions, including lithium chloride (LiCl), lithium bromide (LiBr), lithium nitrite (LiNO2), and lithium nitrate (LiNO3), with methyl thiocyanate as an infrared vibrational probe molecule, using two-dimensional infrared spectroscopy (2D IR), nuclear magnetic resonance (NMR) spectroscopy, and viscometry. The 2D IR, NMR, and viscosity results show that LiNO2 exhibits longer correlation times, lower diffusivity, and nearly 4 times greater viscosity compared to those of the other lithium salt solutions of the same concentration, suggesting that nitrite anions may strongly facilitate structure formation via strengthening water-ion network interactions, directly impacting bulk solution properties at sufficiently high concentrations. Additionally, the LiNO2 and LiNO3 solutions show significantly weakened chemical interactions between the lithium cations and the methyl thiocyanate when compared with those of the lithium halide salts.

A coumarin derived turn ‘off–on-off’ probe for selective sequential monitoring of Al3+ and Cu2+ ions with bio-imaging application

Herein, a coumarin-based chemosensor (E)-N'-(1-(2-oxo-2H-chromen-3-yl)ethylidene) thiophene-2-carbohydrazide (ACT) has been synthesized and thoroughly characterized by using various spectroscopic techniques. The molecular structure of the probe has been confirmed by single crystal X-ray diffraction technique. Hirshfeld surface analysis has also been carried out to investigate weaker interactions in the probe molecule. ACT shows a highly selective enhanced fluorometric response towards Al3+ in ethanol among different competing cations. Upon interaction with Al3+, a new complex ACT-Al3+ is formed which displays a strong yellow fluorescence due to chelation enhanced fluorescence process (CHEF). Furthermore, in situACT-Al3+ complex is exploited for sequential recognition of Cu2+ with fluorescence turn-off via paramagnetic quenching mechanism among different competing cations. This study presents an exceptionally low detection limits of ACT for Al3+ and Cu2+ ions (2.33 × 10−11 and 1.96 × 10−11 M, respectively). Furthermore, the binding constants of ACT for Al3+ and Cu2+ were found to be 7.97 × 104 and 9.79 × 104 M−1, respectively. The binding mechanism has been verified by 1H NMR titration and DFT calculations. Sensing behaviour of ACT towards Al3+ and Cu2+ have also been exploited in the development of paper strip kit and intracellular application in 3rd instar larvae of Drosophila.

Chiral zwitterionic stationary phases based on Cinchona alkaloids and dipeptides: Application in chiral separation of dipeptides under reversed phase conditions

Chromatographic behavior of novel chiral stationary phases with bonded selectors based on Cinchona alkaloids modified with dipeptides was studied using dipeptides as probe molecules. Buffer-free and salt containing hydro-organic solutions were used as the mobile phases. The selectors exhibit pseudoenantiomeric behavior with respect to the L/D or LL/DD enantiomers and do not behave so with respect to the LD/DL enantiomers. The alkaloid part of the selectors is the driver of enantioselectivity, while the dipeptide substituent plays a modulating role. The quinidine-based selectors demonstrate stronger adsorption affinity and higher enantioselectivity as compared to the quinine-based selectors. The dipeptide analytes containing a glycyl fragment are weaker retained and their enantiomers are worse separated comparing to dipeptides with both units being larger amino acids. Moreover, a phenyl group in the structure of a dipeptide analyte facilitates enantioseparation. The effect of the mobile phase composition on retention depends on the hydrophobicity of an analyte. Hydrophobic dipeptides are better eluted by methanol-rich solvents, hydrophilic dipeptides are better eluted with water-rich solvents, and dipeptides with an intermediate hydrophobicity demonstrate a U-shaped or more complicated dependence of the retention factor on the percentage of methanol. Even a small buffer addition to the mobile phase decreases retention, but the ion-exchange mechanism was not confirmed. The effect of an electrolyte is rather due to the shielding of the charged groups of the selector reducing thereby electrostatic interaction between the selector and analyte. Efficiency of the novel columns is comparable to that of other brush-type chiral columns, the highest achieved number of the theoretical plates per 1 m varying between 30,000 and 40,000.

High-performance grating-like SERS substrate based on machine learning for ultrasensitive detection of Zexie-Baizhu decoction

Rapid, universal and accurate identification of chemical composition changes in multi-component traditional Chinese medicine (TCM) decoction is a necessary condition for elucidating the effectiveness and mechanism of pharmacodynamic substances in TCM. In this paper, SERS technology, combined with grating-like SERS substrate and machine learning method, was used to establish an efficient and sensitive method for the detection of TCM decoction. Firstly, the grating-like substrate prepared by magnetron sputtering technology was served as a reliable SERS sensor for the identification of TCM decoction. The enhancement factor (EF) of 4-ATP probe molecules was as high as 1.90 × 107 and the limit of detection (LOD) was as low as 1 × 10−10 M. Then, SERS technology combined with support vector machine (SVM), decision tree (DT), Naive Bayes (NB) and other machine learning algorithms were used to classify and identify the three TCM decoctions, and the classification accuracy rate was as high as 97.78 %. In summary, it is expected that the proposed method combining SERS and machine learning method will have a high development in the practical application of multi-component analytes in TCM.

Pyrazole probes for the detection of N2H4 with ICT properties in live cells and soils

Here, the two novel fluorescent probes Z1 and Z2 have been designed and synthesized based on pyrazole derivative to recognize hydrazine, and the molecular structure was determined by 1H NMR, 13C NMR, and ESI-MS. The obtained probe molecules have AIE and ICT characteristics. Nuclear magnetic resonance analysis (NMR) and theoretical calculations were used to confirm the identification mechanism. Probes Z1 and Z2 have good selectivity, low detection limits (0.197 µM and 0.185 µM, respectively), and high sensitivity. Probes Z1 and Z2 have large Stokes shifts of 198 nm and 211 nm, respectively. The probes also could be made into test paper strips for the detection of hydrazine. Furthermore, the probes can be used in the detection of N2H4 in environmental soil samples and cell imaging. The results showed that the synthetic probe had good biocompatibility. Cell imaging experiments were performed to apply probes to the detection of hydrazine hydrate in HeLa cells.

Decoration of Ag nanoparticle on MXene sheets for SERS studies

MXene sheets with the unique electrical and optical properties show the excellent potential for surface-enhanced Raman spectroscopy (SERS) applications. In this study, we chose Ti3C2Tx, a type of MXene, to decorate silver nanoparticles (Ag NPs) on the ultrathin two-dimensional (2D) MXene sheets. The designed Ag-MXene substrates with SERS activity showed high sensitivity, high stability, and reproducibility. The SERS signal was enhanced by the synergistic contribution of both charge-transfer (CT) and surface plasmon resonance (SPR) involving the Ag NPs and the MXene sheets. Due to the strong interaction between the probe molecules and Ag NPs which provided the nanoscale gap, the substrate exhibited remarkable SERS performance. A novel experimental strategy was developed to facilitate the controlled synthesis of noble metal NPs and MXene sheets and provide insights for further improving the practical applications of these materials in SERS detection.