NIR-II Surface-Enhanced Raman Scattering Nanoprobes in Biomedicine: Current Impact and Future Directions.

The field of second near-infrared (NIR-II) surface-enhanced Raman scattering (SERS) nanoprobes has made commendable progress in biomedicine. This article reviews recent advances and future development of NIR-II SERS nanoprobes. It introduces the fundamental principles of SERS nanoprobes and highlights key advances in the NIR-II window, including reduced tissue attenuation, deep penetration, maximized allowable exposure, and improved photostability. The discussion of future directions includes the refinement of nanoprobe substrates, emphasizing the tailoring of optical properties of metallic SERS-active nanoprobes, and exploring non-metallic alternatives. The intricacies of designing Raman reporters for the NIR-II resonance and the potential of these reporters to advance the field are also discussed. The integration of artificial intelligence (AI) into nanoprobe design represents a cutting-edge approach to overcome current challenges. This article also examines the emergence of deep Raman techniques for through-tissue SERS detection, toward NIR-II SERS tomography. It acknowledges instrumental advancements like improved charge-coupled device sensitivity and accelerated imaging speeds. The article concludes by addressing the critical aspects of biosafety, ease of functionalization, compatibility, and the path to clinical translation. With a comprehensive overview of current achievements and future prospects, this review aims to illuminate the path for NIR-II SERS nanoprobes to innovate diagnostic and therapeutic approaches in biomedicine.

Gold Fluorescence Nanoparticles for Enhanced SERS Detection in Biomedical Sensor Applications: Current Trends and Future Directions.

Nanotechnology has emerged as a pivotal tool in biomedical research, particularly in developing advanced sensing platforms for disease diagnosis and therapeutic monitoring. Since gold nanoparticles are biocompatible and have special optical characteristics, they are excellent choices for surface-enhanced Raman scattering (SERS) sensing devices. Integrating fluorescence characteristics further enhances their utility in real-time imaging and tracking within biological systems. The synergistic combination of SERS and fluorescence enables sensitive and selective detection of biomolecules at trace levels, providing a versatile platform for early cancer diagnosis and drug monitoring. In cancer detection, AuNPs facilitate the specific targeting of cancer biomarkers, allowing for early-stage diagnosis and personalized treatment strategies. The enhanced sensitivity of SERS, coupled with the tunable fluorescence properties of AuNPs, offers a powerful tool for the identification of cancer cells and their microenvironment. This dual-mode detection not only improves diagnostic accuracy but also enables the monitoring of treatment response and disease progression. In drug detection, integrating AuNPs with SERS provides a robust platform for identifying and quantifying pharmaceutical compounds. The unique spectral fingerprints obtained through SERS enable the discrimination of drug molecules even in complex biological matrices. Furthermore, the fluorescence property of AuNPs makes it easier to track medication distribution in real-time, maximizing therapeutic effectiveness and reducing adverse effects. Furthermore, the review explores the role of gold fluorescence nanoparticles in photodynamic therapy (PDT). By using the complementary effects of targeted drug release and light-induced cytotoxicity, SERS-guided drug delivery and photodynamic therapy (PDT) can increase the effectiveness of treatment against cancer cells. In conclusion, the utilization of gold fluorescence nanoparticles in conjunction with SERS holds tremendous potential for revolutionizing cancer detection, drug analysis, and photodynamic therapy. The dual-mode capabilities of these nanomaterials provide a multifaceted approach to address the challenges in early diagnosis, treatment monitoring, and personalized medicine, thereby advancing the landscape of biomedical applications.

SERS biosensors based on catalytic hairpin self-assembly and hybridization chain reaction cascade signal amplification strategies for ultrasensitive microRNA-21 detection.

A highly sensitive surface-enhanced Raman scattering (SERS) biosensor has been developed for the detection of microRNA-21 (miR-21) using an isothermal enzyme-free cascade amplification method involving catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR). The CHA reaction is triggered by the target miR-21, which causes hairpin DNA (C1 and C2) to self-assemble into CHA products. After AgNPs@Capture captures the resulting CHA product, the HCR reaction is started, forming long-stranded DNA on the surface of AgNPs. A strong SERS signal is generated due to the presence of a large amount of the Raman reporter methylene blue (MB) in the vicinity of the SERS "hot spot" on the surface of AgNPs. The monitoring of the SERS signal changes of MB allows for the highly sensitive and specific detection of miR-21. In optimal conditions, the biosensor exhibits a satisfactory linear range and a low detection limit for miR-21 of 42.3 fM. Additionally, this SERS biosensor shows outstanding selectivity and reproducibility. The application of this methodology to clinical blood samples allows for the differentiation of cancer patients from healthy controls. As a result, the CHA-HCR amplification strategy used in this SERS biosensor could be a useful tool for miRNA detection and early cancer screening.

Optimisation of a Microwave Synthesis of Silver Nanoparticles by a Quality by Design Approach to Improve SERS Analytical Performances.

A major limitation preventing the use of surface-enhanced Raman scattering (SERS) in routine analyses is the signal variability due to the heterogeneity of metallic nanoparticles used as SERS substrates. This study aimed to robustly optimise a synthesis process of silver nanoparticles to improve the measured SERS signal repeatability and the protocol synthesis repeatability. The process is inspired by a chemical reduction method associated with microwave irradiation to guarantee better controlled and uniform heating. The innovative Quality by Design strategy was implemented to optimise the different parameters of the process. A preliminary investigation design was firstly carried out to evaluate the influence of four parameters selected by means of an Ishikawa diagram. The critical quality attributes were to maximise the intensity of the SERS response and minimise its variance. The reaction time, temperature and stirring speed are critical process parameters. These were optimised using an I-optimal design. A robust operating zone covering the optimal reaction conditions (3.36 min-130 °C-600 rpm) associated with a probability of success was modelled. Validation of this point confirmed the prediction with intra- and inter-batch variabilities of less than 15%. In conclusion, this study successfully optimised silver nanoparticles by a rapid, low cost and simple technique enhancing the quantitative perspectives of SERS.

Plasmonic Cyclic Au Nanosphere Hexamers.

Rational design of plasmonic colloidal assemblies via bottom-up synthesis is challenging but would show unprecedented optical properties that strongly relate to the assembly's shape and spatial arrangement. Herein, the synthesis of plasmonic cyclic Au nanosphere hexamers (PCHs) is reported, wherein six Au nanospheres (Au NSs) are connected via thin metal ligaments. By tuning Au reduction, six dangling Au NSs are interconnected with a core hexagon nanoplate (NPL). Then, Pt atoms are selectively deposited on the edges of the spheres. After etching of the core, necklace-like nanostructures of Pt framework are obtained. Deposition of Au is followed, leading to PCHs in high yield (≈90%). Notably, PCHs exhibit the combinatorial plasmonic characteristics of individual Au NSs and the in-plane coupling of the six linked Au NSs. They yield highly uniform, reproducible, and polarization-independent single-particle surface-enhanced Raman scattering signals, which are attributed to the 2-dimensional isotropic alignment of the Au NSs. Those are applied to a SERS-based immunoassay as quantitative and qualitative single particle SERS nanoprobes. This assay shows a low limit-of-detection, down to 100 pm, which is orders of magnitude lower than those based on Au NSs, and one order of magnitude lower than an assay using analogous particles of smooth Au nanorings.

Promising Mass-Productive 4-Inch Commercial SERS Sensor with Particle in Micro-Nano Porous Ag/Si/Ag Structure Using in Auxiliary Diagnosis of Early Lung Cancer.

The construction of commercial surface enhanced Raman scattering (SERS) sensors suitable for clinical applications is a pending problem, which is heavily limited by the low production of high-performance SERS bases, because they usually require fine or complicated micro/nano structures. To solve this issue, herein, a promising mass-productive 4-inch ultrasensitive SERS substrate available for early lung cancer diagnosis is proposed, which is designed with a special architecture of particle in micro-nano porous structure. Benefitting from the effective cascaded electric field coupling inside the particle-in-cavity structure and efficient Knudsen diffusion of molecules within the nanohole, the substrate exhibits remarkable SERS performance for gaseous malignancy biomarker, with the limit of detection is 0.1 ppb and the average relative standard deviation value at different scales (from cm2 to µm2 ) is ≈16.5%. In practical application, this large-sized sensor can be further divided into small ones (1 × 1 cm2 ), and more than 65 chips will be obtained from just one 4-inch wafer, greatly increasing the output of commercial SERS sensor. Further, a medical breath bag composed of this small chip is designed and studied in detail here, which suggested high-specificity recognition for lung cancer biomarker in mixed mimetic exhalation tests.

Rapid and simple isolation and detection of exosomes using CaTiO3:Eu3+@Fe3O4 multifunctional nanocomposites.

Exosomes are potential biomarkers for disease diagnosis and treatment, as well as drug carriers. However, as their isolation and detection remain critical issues, convenient, rapid, low-cost, and effective methods are necessary. In this study, we present a rapid and simple method for directly capturing and analyzing exosomes from complex cell culture media using CaTiO3:Eu3+@Fe3O4 multifunctional nanocomposites. The CaTiO3:Eu3+@Fe3O4 nanocomposites were prepared by high-energy ball-milling and used to isolate exosomes by binding CaTiO3:Eu3+@Fe3O4 nanocomposites and the hydrophilic phosphate head of the exosome phospholipids. Notably, the developed CaTiO3:Eu3+@Fe3O4 multifunctional nanocomposites achieved results comparable with those of commercially available TiO2 and were separated using a magnet within 10 min. Moreover, we report a surface-enhanced Raman scattering (SERS)-based immunoassay for detecting the exosome biomarker CD81. Gold nanorods (Au NRs) were modified with detection antibodies, and antibody-conjugated Au NRs were labeled with 3, 3, diethylthiatricarbocyanine iodide (DTTC) as the SERS tags. A method combining magnetic separation and SERS was developed to detect exosomal biomarker CD81. The results of this study demonstrate the feasibility of this new technique as a useful tool for exosome isolation and detection.

A strategy to enhance SERS detection sensitivity through the use of SiO2 beads in a 1536-well plate.

The development of rapid and accurate assays is crucial to prevent the rapid spread of highly contagious respiratory infections such as coronavirus (COVID-19). Here, we developed a surface-enhanced Raman scattering (SERS)-enzyme-linked immunosorbent assay (ELISA) method that allows for the screening of multiple patient samples with high sensitivity on a 1536-well plate. As the well number on the ELISA well plate increases from 96 to 1536, the throughput of the assay increases but the sensitivity decreases due to the low number of biomarkers and the increase in non-specific binding species. To address this problem, silica (SiO2) beads were used to increase the surface-to-volume ratio and the loading density of biomarkers, thereby enhancing sensitivity. Using a three-dimensional gold nanoparticle (AuNP)@SiO2 SERS assay platform on a 1536-well plate, an immunoassay for the nucleocapsid protein biomarker of SARS-CoV-2 was performed and the limit of detection (LoD) decreased from 273 to 7.83 PFU/mL compared to using a two-dimensional assay platform with AuNPs. The proposed AuNPs@SiO2 SERS immunoassay (SERS-IA) platform is expected to dramatically decrease the false-negative diagnostic rate of the currently used lateral flow assay (LFA) or ELISA by enabling the positive diagnosis of patients with low virus concentrations.

Rapid and precise detection of cancers via label-free SERS and deep learning.

Early, express, and reliable detection of cancer can provide a favorable prognosis and decrease mortality. Tumor biomarkers have been proven to be closely related to tumor occurrence and development. Conventional tumor biomarker detection based on genomic, proteomic, and metabolomic methods is time and equipment-consuming and always needs a specific target marker. Surface-enhanced Raman scattering (SERS), as a non-invasive ultrasensitive and label-free vibrational spectroscopy technique, can detect cancer-related biomedical changes in biofluids. In this paper, 110 serum samples were collected from 30 healthy controls and 80 cancer patients (including 30 bladder cancer (BC), 30 adrenal cancer (AC), and 20 acute myeloid leukemia (AML)). One microliter of blood serum was mixed with 1 µl silver colloid and then was air-dried for SERS measurements. After spectral data augmentation, one-dimensional convolutional neural network (1D-CNN) was proposed for precise and rapid identification of healthy and three different cancers with high accuracy of 98.27%. After gradient-weighted class activation mapping (Grad-CAM) based spectral interpretation, the contributions of SERS peaks corresponding to biochemical substances indicated the most potential biomarkers, i.e., L-tyrosine in bladder cancer; acetoacetate and riboflavin in adrenal cancer and phospholipids, amide-I, and α-Helix in acute myeloid leukemia, which might provide an insight into the mechanism of intelligent diagnosis of different cancers based on label-free serum SERS. The integration of label-free SERS and deep learning has great potential for the rapid, reliable, and non-invasive detection of cancers, which may significantly improve the precise diagnosis in clinical practice.

SERS-ELISA using silica-encapsulated Au core-satellite nanotags for sensitive detection of SARS-CoV-2.

The sensitive detection of viruses is key to preventing the spread of infectious diseases. In this study, we develop a silica-encapsulated Au core-satellite (CS@SiO2) nanotag, which produces a strong and reproducible surface-enhanced Raman scattering (SERS) signal. The combination of SERS from the CS@SiO2 nanotags with enzyme-linked immunosorbent assay (ELISA) achieves a highly sensitive detection of SARS-CoV-2. The CS@SiO2 nanotag is constructed by assembling 32 nm Au nanoparticles (AuNPs) on a 75 nm AuNP. Then the core-satellite particles are encapsulated with SiO2 for facile surface modification and stability. The SERS-ELISA technique using the CS@SiO2 nanotags provides a great sensitivity, yielding a detection limit of 8.81 PFU mL-1, which is 10 times better than conventional ELISA and 100 times better than lateral flow assay strip method. SERS-ELISA is applied to 30 SARS-CoV-2 clinical samples and achieved 100% and 55% sensitivities for 15 and 9 positive samples with cycle thresholds < 30 and > 30, respectively. This new CS@SiO2-SERS-ELISA method is an innovative technique that can significantly reduce the false-negative diagnostic rate for SARS-CoV-2 and thereby contribute to overcoming the current pandemic crisis.

Cascaded nanooptics to probe microsecond atomic-scale phenomena.

Plasmonic nanostructures can focus light far below the diffraction limit, and the nearly thousandfold field enhancements obtained routinely enable few- and single-molecule detection. However, for processes happening on the molecular scale to be tracked with any relevant time resolution, the emission strengths need to be well beyond what current plasmonic devices provide. Here, we develop hybrid nanostructures incorporating both refractive and plasmonic optics, by creating SiO2 nanospheres fused to plasmonic nanojunctions. Drastic improvements in Raman efficiencies are consistently achieved, with (single-wavelength) emissions reaching 107 counts⋅mW-1⋅s-1 and 5 × 105 counts∙mW-1∙s-1∙molecule-1, for enhancement factors >1011 We demonstrate that such high efficiencies indeed enable tracking of single gold atoms and molecules with 17-µs time resolution, more than a thousandfold improvement over conventional high-performance plasmonic devices. Moreover, the obtained (integrated) megahertz count rates rival (even exceed) those of luminescent sources such as single-dye molecules and quantum dots, without bleaching or blinking.

Surface-enhanced Raman scattering based determination on sulfamethazine using molecularly imprinted polymers decorated with silver nanoparticles.

Molecularly imprinted polymers (MIPs) were combined with surface-enhanced Raman scattering (SERS) and AgNPs were prepared by in situ reduction within the MIP for selective and sensitive detection of sulfamethazine (SMZ). The MIP@AgNPs composites were characterized in detail by several analytical techniques, showing the generation of polymers and the formation of AgNPs hot spots. The specific affinity and rapid adsorption equilibrium rates of MIP@AgNPs composites were verified by static and kinetic adsorption studies. The MIP@AgNPs with high selectivity and excellent sensitivity were used as SERS substrates to detect SMZ. A good linear correlation (R2 = 0.996) in rang of 10-10-10-6 mol L-1 was observed between the Raman signal (1596 cm-1) and the concentration of SMZ. The limit of detection (LOD) was as low as 8.10 × 10-11 mol L-1 with relative standard deviations (RSD) of 6.32%. The good stability and reproducibility are also fully reflected in the SERS detection based on MIP@AgNPs. The method was successfully applied to the analysis of lake water samples, with recoveries in the range 85.1% to 102.5%. In summary, SERS detection based on MIP@AgNPs can be developed for a wider and broader range of practical applications. Schematic illustration of MIP@AgNPs sensor for the SERS detection of sulfamethazine.

Paper-based substrates for surface-enhanced Raman spectroscopy sensing.

Surface-enhanced Raman scattering (SERS) has been recognized as one of the most sensitive analytical methods by adsorbing the target of interest onto a plasmonic surface. Growing attention has been directed towards the fabrication of various substrates to broaden SERS applications. Among these, flexible SERS substrates, particularly paper-based ones, have gained popularity due to their easy-to-use features by full contact with the sample surface. Herein, we reviewed the latest advancements in flexible SERS substrates, with a focus on paper-based substrates. Firstly, it begins by introducing various methods for preparing paper-based substrates and highlights their advantages through several illustrative examples. Subsequently, we demonstrated the booming applications of these paper-based SERS substrates in abiotic and biological matrix detection, with particular emphasis on their potential application in clinical diagnosis. Finally, the prospects and challenges of paper-based SERS substrates in broader applications are discussed.

PVP-capped silver nanoparticles for efficient SERS detection of adenine based on the stabilizing and enrichment roles of PVP.

A polyvinylpyrrolidone-capped (PVP-capped) strategy is reported to synthesize Ag NPs on silicon wafers via galvanic replacement reaction for SERS detection of adenine, where PVP acts as stabilizing agent in synthesis and efficient enrichment in detection. The morphologies of Ag NPs are optimized with uniform particle size by adjusting synthesis conditions, which hold excellent SERS performances like a high enhancement factor of 1.42 × 106, good uniform, reproducibility, and transferable nature. With the protection of the capped PVP, the Ag NPs keep excellent SERS properties even against harsh conditions of high temperature (100 ℃) and strong acid and base for 24 h. Utilizing the structural feature of PVP with abundant carbonyl groups, the PVP-capped Ag NPs achieve efficient enrichment of adenine through hydrogen bonding and π-interactions, which is analyzed by density functional theory. Quantitative detection of adenine is performed with a wide linear range from 10-4 to 10-8 M and a low limit of detection of 1 nM. Detection of adenine in human urine samples is achieved with a recovery of 99.1-103.4% and an RSD of less than 5%.

SERS Detection of the Anti-Epileptic Drug Perampanel in Human Saliva.

Surface-Enhanced Raman Scattering (SERS) can obtain the spectroscopic response of specific analytes. In controlled conditions, it is a powerful quantitative technique. However, often the sample and its SERS spectrum are complex. Pharmaceutical compounds in human biofluids with strong interfering signals from proteins and other biomolecules are a typical example. Among the techniques for drug dosage, SERS was reported to detect low drug concentrations, with analytical capability comparable to that of the assessed High-Performance Liquid Chromatography. Here, for the first time, we report the use of SERS for Therapeutic Drug Monitoring of the Anti-Epileptic Drug Perampanel (PER) in human saliva. We used inert substrates decorated with gold NPs deposited via Pulsed Laser Deposition as SERS sensors. We show that it is possible to detect PER in saliva via SERS after an optimized treatment of the saliva sample. Using a phase separation process, it is possible to extract all the diluted PER in saliva from the saliva phase to a chloroform phase. This allows us to detect PER in the saliva at initial concentrations of the order of 10-7 M, thus approaching those of clinical interest.

A Dual-Modal Single-Antibody Plasmonic Spectro-Immunoassay for Detection of Small Molecules.

Small molecules play a pivotal role in regulating physiological processes and serve as biomarkers to uncover pathological conditions and the effects of therapeutic treatments. However, it remains a significant challenge to detect small molecules given the size as compared to macromolecules. Recently, the newly emerging plasmonic immunoassays based on surface-enhanced Raman scattering (SERS) offer great promise to deliver extraordinary sensitivity. Nevertheless, they are limited by the intrinsic SERS intensity fluctuations associated with the SERS uncertainty principle. The single transducer that relies on the intensity change is also prone to false signals. Additionally, the prevailing sandwich immunoassay format proves less effective towards detecting small molecules. To circumvent these critical issues, a dual-modal single-antibody approach that synergizes both the intensity and shift of the peak-based immunoassay with Raman enhancement, coined as the INSPIRE assay, is developed for small molecules detection. With two independent transduction mechanisms, it allows better prediction of analyte concentration and attenuation of signal artifacts, providing a new and robust strategy for molecular analysis. With a proof-of-concept demonstration for detection of free T4 and testosterone in serum matrix, the authors envision that the INSPIRE assay could be expanded for a wide spectrum of applications in biomedical diagnosis, discovery of new biopharmaceuticals, food safety, and environmental monitoring.

Progress on aptamer-based SERS sensors for food safety and quality assessment: methodology, current applications and future trends.

It is well known that food safety has aroused extensive attentions from governments to researchers and to food industries. As a versatile technology based on molecular interactions, aptamer sensors which could specifically identify a wide range of food contaminants have been extensively studied in recent years. Surface-enhanced Raman spectroscopy integrated aptamer combines the advantages of both technologies, not only in the ability to specifically identify a wide range of food contaminants, but also in the ultra-high sensitivity, simplicity, portable and speed. To provide beneficial insights into the evaluation techniques in the field of food safety, we offer a comprehensive review on the design strategies for aptamer-SERS sensors in different scenarios, including non-nucleic acid amplification methods ("on/off" mode, sandwich mode, competition model and catalytic model) and nucleic acid amplification methods (hybridization chain reaction, rolling circle amplification, catalytic hairpin assembly). Meanwhile, a special attention is paid to the application of aptamer-SERS sensors in biological (foodborne pathogenic, bacteria and mycotoxins) and chemical contamination (drug residues, metal ions, and food additives) of food matrix. Finally, the challenges and prospects of developing reliable aptamer-SERS sensors for food safety were discussed, which are expected to offer a strong guidance for further development and extended applications.

Surface-enhanced Raman Scattering of Au-Ag bimetallic nanopillars fabricated using surface-plasmon lithography.

Arrays of gold-silver (Au-Ag) bimetallic nanopillars were fabricated by a newly developed surface-plasmon lithography (SPL) and their enhancement properties as surface-enhanced Raman scattering (SERS) substrates have been studied. We demonstrated that the SPL is a low-cost and high efficiency method for the fabrication of SERS substrates with both high sensitivity and reproducibility. The nanopillars showed a good response in the detection of methylene blue molecules at a low concentration of 1.0 × 10-11mol· l-1. The SERS enhancement factors (EFs) are on the orders of 107and the relative standard deviation of SERS intensity is <8% over an area of 50µm × 50µm. The EFs increase fast with the height increasing from 200 to 530 nm, then increase slowly when further increase the height of the nanopillars to 1100 nm. In addition, the Au-Ag bimetallic coating has shown much higher SERS enhancement than the coatings of either the pure Au or Ag. The excellent SERS enhancement and reproducibility of the Au-Ag coated nanopillars indicated that the fabricated SERS substrates can be used for the detection of biochemical molecules at trace level and the SPL is a promising method for fabrication of SERS substrates.

An antigen-targeting assay for Lyme disease: Combining aptamers and SERS to detect the OspA protein.

Lyme disease is the fastest growing vector-borne disease in the United States. However, current testing modalities are ill suited to detection of Lyme disease, leading to the diagnosis of many cases after treatment is effective. We present an improved, direct method Lyme disease diagnosis, where the Lyme specific biomarker Outer Surface Protein A (OspA) in clinical serum samples is identified using a diagnostic platform combining surface enhanced Raman scattering (SERS) and aptamers. Employing orthogonal projections to latent structures discriminant analysis, the system accurately identified 91% of serum samples from Lyme patients, and 96% of serum samples from symptomatic controls. In addition, the OspA limit-of-detection, determined to be 1 × 10-4 ng/mL, is greater than four orders of magnitude lower than that found in serum samples from early Lyme disease patients. The application of this platform to detect this difficult-to-diagnose disease suggests its potential for detecting other diseases that present similar difficulties.

Surface-Enhanced Raman Scattering (SERS) Taster: A Machine-Learning-Driven Multireceptor Platform for Multiplex Profiling of Wine Flavors.

Integrating machine learning with surface-enhanced Raman scattering (SERS) accelerates the development of practical sensing devices. Such integration, in combination with direct detection or indirect analyte capturing strategies, is key to achieving high predictive accuracies even in complex matrices. However, in-depth understanding of spectral variations arising from specific chemical interactions is essential to prevent model overfit. Herein, we design a machine-learning-driven "SERS taster" to simultaneously harness useful vibrational information from multiple receptors for enhanced multiplex profiling of five wine flavor molecules at parts-per-million levels. Our receptors employ numerous noncovalent interactions to capture chemical functionalities within flavor molecules. By strategically combining all receptor-flavor SERS spectra, we construct comprehensive "SERS superprofiles" for predictive analytics using chemometrics. We elucidate crucial molecular-level interactions in flavor identification and further demonstrate the differentiation of primary, secondary, and tertiary alcohol functionalities. Our SERS taster also achieves perfect accuracies in multiplex flavor quantification in an artificial wine matrix.