First report! A New Method for Detection of Covid-19 S Protein-Surface Raman Sensitive Detection Based on MXenes

Surface Enhanced Raman Scattering (SERS), as a powerful spectroscopic detection technology, has attracted widespread attention in the fields of chemical and biological analysis. Because of its high sensitivity, non-destructive, trace, real-time rapid detection and other advantages, it is expected to develop into a practical detection technology, especially in the field of virus detection and biosensing, which has broad application prospects. Virus infection has always been a serious threat to human health, especially the COVID-19 outbreak caused by the new coronavirus in December 2019. Many countries have reported the detection of new coronaviruses in polluted water bodies, and pointed out that the detection of viruses in polluted water bodies is expected to reveal the true scale of coronavirus infections, thereby effectively controlling the spread of new coronaviruses. Therefore, sensitive detection and accurate identification of the new coronavirus in patients  body fluids or contaminated water is the key to real-time monitoring and early warning of the virus.

Highlights of this article

1. It is the first report that Nb₂C and Ta₂C MXenes have excellent SERS performance, and their SERS enhancement factors can reach 3.0×10⁶ and 1.4×10⁶, respectively. This is due to the synergistic effect of light-induced charge transfer resonance enhancement and electromagnetic enhancement.

2. Based on the excellent SERS sensitivity of Ta₂C MXene, the SERS detection of the new coronavirus S protein and the accurate identification of its Raman peak have been completed, which is conducive to real-time monitoring and early warning of the new coronavirus.

brief introduction

The team of Yang Yong and Huang Zhengren, Shanghai Institute of Ceramics, Chinese Academy of Sciences, based on the large specific surface area, high carrier mobility, high electron density of states at the Fermi level and the multi-coordination of Nb⁵⁺ and Ta⁵⁺ based on the MXenes material The advantages of extranuclear excited state electrons with more cations in the field of SERS have unearthed the new SERS active materials of Nb₂C and Ta₂C MXene. Through theoretical simulations, it is predicted that Nb₂C and Ta₂C MXene substrates are expected to exhibit excellent SERS activity due to the synergistic effects of charge transfer resonance enhancement and electromagnetic enhancement, and their optimal resonance excitation wavelength is predicted to be 532 nm. Under the guidance of theoretical prediction results, it is reported for the first time that Nb₂C and Ta₂C MXenes have excellent SERS sensitivity, and their SERS enhancement factors have been successfully optimized to reach 3.0×10⁶ and 1.4×10⁶. In particular, the detection limit of Nb₂C for MeB molecules is as low as 10⁻⁸ M, which is excellent in the reported pure MXene substrates excited by 532 nm laser. And thanks to the excellent SERS sensitivity of the MXene material, the team has completed the sensitive detection of the new coronavirus S protein and accurate identification of the Raman peak, and its detection limit can be as low as 5×10⁻⁹ mol/L, which is a The real-time monitoring and early warning of the new coronavirus based on SERS technology is of great significance.

Graphic guide

Theoretical prediction of I SERS activity

Recent studies have shown that the mechanism of Raman enhancement of two-dimensional material-based SERS substrates is mainly CM chemical enhancement mechanism, and CM determines the molecular selectivity and vibration selectivity of SERS. In this paper, the contribution of CM to SERS activity is characterized by calculating static Raman spectra, charge difference distribution and molecular orbitals. Molecular adsorption on Nb₂C and Ta₂C clusters can form chemical bonds between transition metal atoms and non-metal atoms, which act as charge transfer channels to promote the redistribution of electron clouds around molecules and MXene clusters. Therefore, when the molecules are absorbed on the Nb₂C and Ta₂C clusters, their HOMO-LUMO energy gaps are significantly reduced to 2.16 eV and 2.35 eV, corresponding to the optimal resonance excitation wavelength of 532 nm. Based on the finite difference time domain (FDTD) solution, the electromagnetic field distribution is calculated to characterize the contribution of EM to SERS activity. Obviously, a strong enhanced electric field can be observed at the edge of the ring-shaped stacked nanosheets, and its strongest electric field enhancement factor on the XY cross-section has the following relationship: Ti₃C₂₂C₂C. In summary, Nb₂C and Ta₂C MXene substrates exhibit excellent SERS activity due to the synergistic contribution of photo-induced charge transfer resonance enhancement and electromagnetic enhancement at the optimal resonance excitation wavelength of 532 nm.

Figure 1. (a) Static Raman spectra of molecules 4-MBA, MeB, MV and the complexes Nb₂C-4-MBA, Ta₂C-4-MBA, Nb₂C-MeB, Ta₂C-MeB, Nb₂C-MV, Ta₂C-MV. Comparing the Raman enhancement multiples of (b) Nb₂C-4-MBA, Nb₂C-MeB, Nb₂C-MV and (c) Ta₂C-based complexes calculated under the Raman displacement of A, B, and C Raman models. (d) Molecules 4-MBA, MeB, MV, and the calculated polarizabilities of these molecules adsorbed on Nb₂C and Ta₂C clusters respectively. (e) Energy level distribution and HOMO/LUMO diagram of 4-MBA, MeB, MV molecule, Nb₂C-4-MBA, Nb₂C-MeB, Nb₂C-MV, Ta₂C-4-MBA, Ta₂C-MeB, Ta₂C-MV complex .

Figure 2. (a) MXene (Ti₃C₂, Nb₂C and Ta₂C) electric field intensity distribution simulation model. (b) The simulated electric field intensity distribution of MXene (Ti₃C₂, Nb₂C and Ta₂C) and the corresponding SERS enhancement factor. The color bar represents the electric field strength.

II Preparation and characterization of Nb₂C/Ta₂C MXenes

In this work, in order to ensure the P63/mmc space group of Nb₂C and Ta₂C MXenes, HF etching of Al atoms and tetrapropylammonium hydroxide (TPAOH) nested dissolution method was used to realize the synthesis of 2D MXene nanosheets. The SEM image shows the typical layered structure of Nb₂C and Ta₂C MXenes, in which several exfoliated nano flakes are stacked into blocks. In addition, the TEM image also shows the formation of a layered structure, although the thickness is quite large. The HRTEM images of the multilayer Nb₂C and Ta₂C MXenes showed a clear crystal lattice, corresponding to the (100) plane and (004) plane of the hexagonal structure, and the plane spacing was 0.269 nm and 0.356 nm, respectively. In order to promote charge transfer and increase the amount of probe molecules adsorbed, the TPAOH chemical dissolution method was used to increase the specific surface area of the MXene nanosheets. After TPAOH is chemically peeled off, the SEM images of Nb₂C and Ta₂C show a layered morphology with significantly increased interlayer distance. In addition, compared with the MXene material before peeling, the TEM image also shows an electronically transparent flake-like structure and thickness. The difference from the SAED image before TPAOH chemical peeling is that the SAED image after peeling tends to form polycrystalline diffraction rings due to the superposition of nanosheets with different orientations.

Figure 3. (a) Schematic diagram of Nb₂C and Ta₂C nanosheets synthesized by a two-step lift-off process. (b) SEM images of Nb₂AlC (1) and Ta₂AlC (3) bulk structures, TEM images of Nb₂AlC (2) and Ta₂AlC (4) bulk structures and corresponding SAED images. (c) SEM image (1), TEM image (2), HRTEM image (3) of Nb₂C and (d) Ta₂C and corresponding SAED mode (4). (e) Scanning electron microscope image, TEM image and corresponding SAED mode of layered d-Nb₂C (1) and d-Ta₂C (3).

III Experimental investigation of Nb₂C/Ta₂C MXenes SERS activity

Under the guidance of theoretical calculations, the SERS performance of Nb₂C and Ta₂C MXenes was studied. First, in order to verify the higher SERS sensitivity of Nb₂C MXene to MeB molecules and Ta₂C MXene to MV molecules under the optimal resonance excitation wavelength radiation, this work studied the molecules on the MXene substrate with different excitation wavelengths of 532, 633 and 785 nm. Raman enhancement effect of radiation. It was found that the Raman enhancement effect of the MeB molecules on the Nb₂C MXene substrate and the MV molecules on the Ta₂C MXene substrate under the excitation laser of 532 nm was significantly stronger than the excitation of the other two excitation wavelength bands (633 and 785 nm). Consistent with the theoretical prediction results. The Nb₂C MXene substrate showed stronger SERS enhancement to MeB molecules, while the Raman intensity of Ta₂C-MV complex was significantly higher than the other two molecules. This conclusion is consistent with the calculated results of static Raman spectroscopy. In addition, according to the Raman mapping of the 10⁻⁵ M MeB molecule on the Nb₂C MXene substrate at 1617 cm⁻¹, the relative standard deviation (RSD) is 6.0%, indicating that the enhancement effect of the molecular Raman signal has good uniformity .

Figure 4. (a) Raman schematic of Raman scattering of MeB and MV molecules using Nb₂C/Ta₂C NSs as a substrate under a 532 nm excitation laser. The Raman spectra of (b) 10⁻⁵ M MeB on the Nb₂C NSs substrate and (e) 10⁻⁵ M MV on the Ta₂C NSs substrate under different wavelength laser excitation at 532, 633 and 785 nm. (c) Nb₂C NSs and (f) Ta₂C NSs substrates Raman spectra of 10⁻⁵ M 4-MBA, MeB, MV under excitation at 532 nm. (d) Select 20 points from the Nb₂C NSs substrate to collect the Raman signal of 10⁻⁵ M MeB and the corresponding Raman mapping image of 1617 cm⁻¹.

IV Experimental Investigation on Sensitivity of Nb₂C/Ta₂C MXenes SERS

In order to explore the SERS sensitivity of the MXene substrate, this work detected the Raman spectra of different concentrations of probe molecules adsorbed on the substrate. For MeB molecules, even if the molar concentration is diluted to 10⁻⁸ M, a weak Raman signal can still be detected when adsorbed on the Nb₂C MXene substrate. When the concentration of the MV solution is diluted to 10⁻⁷ M, it is adsorbed on the Ta₂C MXene substrate, and the Raman signal is greatly enhanced. Under 532 nm laser excitation, the SERS enhancement factors EFs of 10⁻⁷ M MeB and 10⁻⁶ M MV molecules on the Nb₂C MXene substrate are 3.0×10⁶ and 1.5×10⁵. For Ta₂C MXene substrate, the SERS enhancement factors of 10⁻⁶ M MeB and 10⁻⁷ M MV are 3.8×10⁵ and 1.4×10⁶, respectively. In addition, a surprising result is that MV has lower detection limits on Ta₂C MXene and MeB on Nb₂C MXene substrates, 10⁻⁷ M and 10⁻⁸ M, in the currently reported SERS active semiconductor substrates. At a relatively excellent level, it shows the potential for practical applications. In addition, this work is also the first report that Nb₂C and Ta₂C MXene substrates exhibit excellent SERS sensitivity.

 
Figure 5. (a) The Raman spectra of MeB at three different concentrations of 10⁻⁶, 10⁻⁷, and 10⁻⁸ M on Nb₂C NSs substrate. (b) Raman spectra of 10⁻⁵ and 10⁻⁶ M MV on the Nb₂C NSs substrate. (c) Raman spectra of 10⁻⁵ and 10⁻⁶ M MeB on Ta₂C NSs substrate. (d) Raman spectra of MV at three concentrations of 10⁻⁵, 10⁻⁶, 10⁻⁷ M on Ta₂C NSs substrate.

V.  SERS detection of SARS-CoV-2 S protein

Thanks to the excellent SERS sensitivity of Nb₂C and Ta₂C MXenes, they can not only be applied to the detection of organic pollutants in the water environment, but also can be considered for the rapid detection of virus particles. As shown in Figure 6a, the diluted SARS-CoV-2 S protein molecules were adsorbed on Nb₂C and Ta₂C MXenes for Raman detection. However, due to the selectivity of Nb₂C and Ta₂C MXenes substrates to the SERS enhancement of molecules, Ta₂C MXene has more excellent SERS enhancement on SARS-CoV-2 S protein. And its detection limit is as low as 5×10⁻⁹ mol/L, which is conducive to the detection of SARS-CoV-2 S protein through SERS technology to control the spread of the new coronavirus in the environment. In order to more accurately identify the Raman peak of the SARS-CoV-2 S protein on the Ta₂C MXene substrate, this work uses the Raman spectrum of the SARS-CoV-2 S protein on the Au nanoparticle substrate as a reference. The analysis results show that the Raman peaks of the Ta₂C MXene substrate and the SARS-CoV-2 S protein on the gold nanoparticles can be completely matched. However, due to the difference in the SERS enhancement mechanism and the difference in the amount of charge transfer between the two SERS substrates, some Raman peaks will be shifted. The results of Raman mode analysis show that the significant enhancement of the Raman peak of SARS-CoV-2 S protein is mainly attributed to the Raman vibration modes of the three amino acids Tyr, Trp and Phe. In addition, from the number of amino acids in the SARS-CoV-2 S protein gene sequence, it can be seen that Tyr, Trp and Phe are rich in three amino acids. Therefore, DFT can be used to calculate the static Raman spectra and polarizability of amino acids and their corresponding Ta₂C-amino acid complexes to verify the vibration mode of the Raman peak, and analyze the SERS enhancement effect of Ta₂C MXene on Phe, Trp, Tyr and other amino acids . From the static Raman spectrum (Figure 6d), it can be seen that the Raman vibration modes of the Ta₂C-Phe, Ta₂C-Trp, and Ta₂C-Tyr complexes completely match the experimental Raman peak, which theoretically verifies the SARS-CoV-2 S Accuracy of protein Raman peak recognition. In short, the use of Ta₂C MXene substrate has completed the sensitive detection of the SARS-CoV-2 S protein and the accurate identification of the Raman peak, which is of great significance for the real-time monitoring and early warning of the new coronavirus based on SERS technology.

Figure 6. (a) Ta₂C NSs Raman scatter plot of SARS-CoV-2 S protein under 633 nm excitation laser. (b) Raman spectra of the Ta₂C NSs substrate of 10⁻⁹ M SARS-CoV-2 S protein excited by different laser wavelengths at 532 nm, 633 nm and 785 nm. (c) Static Raman spectra of Phe, Trp, Tyr amino acid molecules and their corresponding Ta₂C-amino acid molecular complexes, and experimental Raman spectra of SARS-CoV-2 S protein on Ta₂C NSs. (d) SARS-CoV-2 S protein in Ta₂C NSs

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