Surface-enhanced Raman Scattering Imaging Research Articles

Comparison of Gap-Enhanced Raman Tags and Nanoparticle Aggregates with Polarization Dependent Super-Resolution Spectral SERS Imaging.

Strongly confined electric fields resulting from nanogaps within nanoparticle aggregates give rise to significant enhancement of surface-enhanced Raman scattering (SERS). Nanometer differences in gap sizes lead to drastically different confined field strengths; so much attention has been focused on the development and understanding of nanostructures with controlled gap sizes. In this work, we report a novel petal gap-enhanced Raman tag (GERT) consisting of a bipyramid core and a nitrothiophenol (NTP) spacer to support the growth of hundreds of small petals and compare its SERS emission and localization to a traditional bipyramid aggregate. To do this, we use super resolution spectral SERS imaging that simultaneously captures the SERS images and spectra while varying the incident laser polarization. Intensity fluctuations inherent of SERS enabled super resolution algorithms to be applied, which revealed subdiffraction limited differences in the localization with respect to polarization direction for both particles. Interestingly, however, only the traditional bipyramid aggregates experienced a strong polarization dependence in their SERS intensity and in the plasmon-induced conversion of NTP to dimercaptoazobenzene (DMAB), which was localized with nanometer precision to regions of intense electromagnetic fields. The lack of polarization dependence (validated through electromagnetic simulations) and surface reactions from the bipyramid-GERTs suggests that the emissions arising from the bipyramid-GERTs are less influenced by confined fields.

Targeted SERS Imaging and Intraoperative Real-Time Elimination of Microscopic Tumors for Improved Breast-Conserving Surgery.

Breast-conserving surgery is the favorable option for breast cancer patients owing to its advantages of less aggressiveness and better cosmetic outcomes over mastectomy. However, it often suffers from postsurgical lethal recurrence due to the incomplete removal of microscopic tumors. Here, a surface-enhanced Raman scattering (SERS) surgical strategy is reported for precise delineation of tumor margins and intraoperative real-time elimination of microscopic tumor foci, which is capable of complete surgical removal of breast tumors and significantly improve the outcomes of breast-conserving surgery without local tumor recurrence. The technique is chiefly based on the human epidermal growth factor receptor 2 (HER2)-targeting SERS probes with integrated multifunctionalities of ultrahigh sensitive detection, significant HER2 expression suppression, cell proliferation inhibition, and superior photothermal ablation. In a HER2+ breast tumor mouse model, the remarkable capability of the SERS surgical strategy for complete removal of HER2+ breast tumors through SERS-guided surgical resection and intraoperative real-time photothermal elimination is demonstrated. The results show complete eradiation of HER2+ breast tumors without local recurrence, consequently delivering a 100% tumor-free survival. Expectedly, this SERS surgical strategy holds great promise for clinical treatment of HER2+ breast cancer with improved patients' survival.

Surface-enhanced Raman scattering-fluorescence dual-mode probes for target imaging of tumors, organoids and cancerous cells

A dual-mode nanoprobe (DMNP) overcomes the limitations of single probes and offers superior performance by combining their advantages. Herein, we report a DMNP design that features a gold nanosphere core and two layers of silica wrapping. The gold core surface is coated with 4-mercaptobenzoic acid(4-MBA), which serves as a Raman reporter. After the initial silica encapsulation, fluorophores in the form of conjugated polymer nanoparticles (CPNs) are applied to the surface. Finally, the encapsulation process is completed by adding the second layer of silica. The probe has dual-mode capabilities, including surface-enhanced Raman scattering (SERS) with a Raman enhancement factor of 134.1, and metal-enhanced fluorescence (MEF) with a fluorescence enhancement factor of 1.42. When modified with glycoprotein-3 (GPC3) antibody, the DMNPs probe shows excellent performance in fluorescence and SERS imaging for HepG2 liver cancer cells. When DMNP is conjugated with the breast tumor-specific antibody CA153, the DMNPs-AbCA153 probe enables imaging and induces apoptosis of breast cancer cells. These probes can serve as a platform for visualizing the distribution of cancer cell surface markers by modifying antibodies to recognize the cell surface. They have also shown significant potential as probes for oncology diagnosis and treatment monitoring.

Single-cell SERS imaging of dual cell membrane receptors expression influenced by extracellular matrix stiffness

Membrane receptors perform a diverse range of cellular functions, accounting for more than half of all drug targets. The mechanical microenvironment regulates cell behaviors and phenotype. However, conventional analysis methods of membrane receptors often ignore the effects of the extracellular matrix stiffness, failing to reveal the heterogeneity of cell membrane receptors expression. Herein, we developed an in-situ surface-enhanced Raman scattering (SERS) imaging method to visualize single-cell membrane receptors on substrates with different stiffness. Two SERS substrates, Au@4-mercaptobenzonitrile@Ag@Sgc8c and Au@4-pethynylaniline@Ag@SYL3c, were employed to specifically target protein tyrosine kinase-7 (PTK7) and epithelial cell adhesion molecule (EpCAM), respectively. The polyacrylamide (PA) gels with tunable stiffness (2.5–25 kPa) were constructed to mimic extracellular matrix. The simultaneous SERS imaging of dual membrane receptors on single cancer cells on substrates with different stiffness was achieved. Our findings reveal decreased expression of PTK7 and EpCAM on cells cultured on stiffer substrates and higher migration ability of the cells. The results elucidate the heterogeneity of membrane receptors expression of cells cultured on the substrates with different stiffness. This single-cell analysis method offers an in-situ platform for investigating the impacts of extracellular matrix stiffness on the expression of membrane receptors, providing insights into the role of cell membrane receptors in cancer metastasis.

Mesoporous Silica-Layered Gold Nanorod Core@Silver Shell Nanostructures for Intracellular SERS Imaging and Phototherapy.

Precision diagnosis-guided efficient treatment is crucial to extending the lives of cancer patients. The integration of surface-enhanced Raman scattering (SERS) imaging and phototherapy into a single nanoplatform has been considered a more accurate diagnosis and treatment strategy for cancer nanotheranostics. Herein, we constructed a new type of mesoporous silica-layered gold nanorod core@silver shell nanostructures loaded with methylene blue (GNR@Ag@mSiO2-MB) as a multifunctional nanotheranostic agent for intracellular SERS imaging and phototherapy. The synthesized GNR@Ag@mSiO2-MB nanostructures possessed a uniform core-shell structure, strong near-infrared (NIR) absorbance, photothermal conversion efficiency (65%), dye loading ability, SERS signal, and Raman stability under phototherapy conditions. Under single 785 nm NIR laser irradiation, the intracellular GNR@Ag@mSiO2-MB nanostructures were dramatically decreased to <9%, which showed excellent photothermal and photodynamic effects toward cancer cell killing, indicating that the combination of photothermal therapy (PTT) and photodynamic therapy (PDT) of the GNR@Ag@mSiO2-MB nanostructures could greatly enhance the therapeutic efficacy of cancer cell death. GNR@Ag@mSiO2-MB nanostructures demonstrated a strong Raman signal at 450 and 502 cm-1, corresponding to the δ(C-N-C) mode, suggesting that the Raman bands of GNR@Ag@mSiO2-MB nanostructures were more efficient to detect CT-26 cell SERS imaging with high specificity. Our results indicate that GNR@Ag@mSiO2-MB nanostructures offer an excellent multifunctional nanotheranostic platform for SERS imaging and synergistic anticancer phototherapy in the future.

In situ SERS imaging of protein-specific glycan oxidation on living cells to quantitatively visualize pathogen–cell interactions

A SERS imaging strategy is developed to quantitatively visualize the protein-specific glycan oxidation mediated pathogen–cell interactions and pathogen-resistance mechanisms.

In situ synthesis of gold nanoparticles on layered double hydroxide nanoparticles for multiplexing molecular imaging of single cells

Quasi-spherical gold nanoparticles (AuNPs) are the most widely used surface-enhanced Raman scattering (SERS) nanotags. However, their surface plasmon resonance properties are significantly restricted by their poor colloidal stability in biological media. Herein, we developed a new strategy for in situ synthesis of AuNPs on layered double hydroxide (LDH) nanoparticles to improve the colloidal stability of AuNPs for SERS imaging with multiplexing capability using single laser excitation. The hybridized LDH-AuNPs were constructed via in situ growth of AuNPs on lactic acid-LDH nanoparticles. The size of AuNPs was tuned by changing the concentration of LDH. The LDH-AuNPs were further functionalized with Raman reporter molecules (Ra) to obtain LDH-AuNPs-Ra as SERS nanotags, which were examined in terms of the colloidal stability and photostability in biological media as well as cellular uptake in J774A.1 macrophage cell culture by single cell mapping via confocal Raman microscopy. The cellular uptake of multiple LDH-AuNPs-Ra functionalized with different Raman reporter molecules were further investigated, where the multiplexing capability of SERS assay endows simultaneous detection of multiple LDH-AuNPs-Ra distribution after cellular uptake for cell imaging. In summary, the LDH-supported in situ synthesis of AuNPs have shown the merits of stabilizing AuNPs by using LDH for SERS imaging, as well as demonstrating the multiplexing molecular imaging of single cells. This work thus provides a promising strategy and a new bioimaging nanoplatform for various biomedical studies in the near future.

Surface‐enhanced Raman imaging of intact cancer cell membrane on a rough aluminum substrate

AbstractThe plasma membrane of cancer cells displays differences in lipid and protein composition which distinguish them from healthy cells. Certain molecules have such prominent vibrational characteristics that they can be considered cancer biomarkers. Although Raman spectroscopy is a label‐free non‐invasive method of chemical analysis, it, however, has been limited by weak signals from the membrane compared to the bulk interior of cells. Surface‐enhanced Raman scattering (SERS) on plasmonic gold and silver substrates has previously been used to overcome this limitation. However, the high cost, poor repeatability, and toxicity of these noble metals hinder their practical applications. These challenges may be solved by using different materials and nanostructures. Here, we performed SERS imaging of ovarian cancer cells on rough aluminum substrates and extracted the Raman signals of intact cell membranes by comparing these with the corresponding measurements on Si substrates. We used atomic force microscopy (AFM) for Raman signal calibration. The comparison of cancer and normal cell membranes revealed the different lipid/protein peak ratios in cytoplasm and nucleus‐proximal areas. These Raman signatures of the ovarian cancer can be used as new biomarkers. This method may be extended to other types of cancer biosensing based on aluminum plasmonics.

Label-Free Surface-Enhanced Raman Scattering Bioanalysis Based on Au@Carbon Dot Nanoprobes.

Surface-enhanced Raman scattering (SERS) technology has attracted more and more attention in the biomedical field due to its ability to provide molecular fingerprint information of biological samples, as well as its potential in single-cell analysis. This work aims to establish a simple strategy for label-free SERS bioanalysis based on Au@carbon dot nanoprobes (Au@CDs). Here, polyphenol-derived CDs are utilized as the reductant to rapidly synthesize core-shell Au@CD nanostructures, which allows powerful SERS performance even when the concentration of methylene blue (MB) is as low as 10-9 M, due to the cooperative Raman enhancement mechanism. For bioanalysis, Au@CDs can serve as a unique SERS nanosensor to identify the cellular components of biosamples (e.g., cancer cells and bacteria). The molecular fingerprints from different species can be further distinguished after combination with the principal component analysis. In addition, Au@CDs also enable label-free SERS imaging to analyze intracellular composition profiles. This strategy offers a feasible, label-free SERS bioanalysis, opening up a new prospect for nanodiagnosis.

Additive Manufacturing‐Enabled Architected Nanocomposite Lattices Coated with Plasmonic Nanoparticles for Water Pollutants Detection

AbstractNovel low‐cost materials to uptake and detect vestigial amounts of pesticides are highly desirable for water quality monitoring. Herein, are demonstrated, for the first time, surface‐enhanced Raman scattering (SERS) sensors enabled via additively manufactured lattices coated with plasmonic nanoparticles (NPs) for detecting pesticides in real water samples. The architected lattices comprising polypropylene (PP) and multiwall carbon nanotubes (MWCNTs) are realized via fused filament fabrication (FFF). In the first stage, the SERS performance of the PP/MWCNT filaments coated with distinct metallic NPs (Ag NPs and Au NPs) is evaluated using methylene blue (MB) as molecular probe. Thereafter, distinctly architected hybrid SERS sensors with periodic porous and fully dense geometries are investigated as adsorbents to uptake MB from aqueous solutions and subsequent detection using SERS. The spatial distribution of MB and Ag NPs on the FFF‐printed lattices is accomplished by SERS imaging. The best hybrid composite is used as SERS probing system to detect low amounts of pesticides (thiram and paraquat) and offers a detection limit of 100 nm for both pesticides. As a proof‐of‐concept, FFF‐enabled test strips are used to detect in loco paraquat molecules spiked on real water samples (Estuary Aveiro water and tap water) using a portable Raman spectrometer.

Recent research progress of surface enhanced Raman scattering dominated analysis strategy in early diagnosis of diseases.

Timely and powerful diagnostic means can achieve better therapeutic effects, reduce disease torment, and improve survival rate. As a powerful non-invasive spectroscopy technology, surface-enhanced Raman scattering (SERS) have testified to be a great potential candidate for extensive early clinical disease diagnosis. In recent years, the introduction of SERS label, combined with other analysis modes or artificial intelligence, and the emergence of miniaturized devices have made SERS technology more advantageous in early diagnosis of diseases. This review focuses on the research progress of SERS dominated analytical strategies in the field of early disease diagnosis in the past five years. The main content includes the application of label-free SERS detection; the construction of label SERS methodologies for various disease markers; SERS dominated multimode early disease diagnosis strategies; integration of SERS and artificial intelligence; portable Raman equipment and SERS imaging; opportunities and trends for SERS diagnostic technology in the future.

A Multilayered Mesoporous Gold Nanoarchitecture for Ultraeffective Near‐Infrared Light‐Controlled Chemo/Photothermal Therapy for Cancer Guided by SERS Imaging (Small 6/2023)

Chemo/Photothermal Therapy for Cancer Guided by SERS Imaging In article number 2206762, Mo Yang, Siu Hong Dexter Wong, and co-workers develop a multilayered mesoporous gold nanoarchitecture labeled with Raman reporters for ultraeffective surface-enhanced Raman scattering (SERS) imaging-guided synergistic therapy toward cancer. This nanoplatform enables efficient xenograft tumor model targeting with sensitive SERS imaging in vitro and in vivo for identifying the tumor cells and optimal therapeutic time point, thereby achieving the highest therapeutic outcome of noninvasive near-infrared triggered photothermal therapy and hyperthermia enhanced chemotherapy.

New Model for Quantifying the Nanoparticle Concentration Using SERS Supported by Multimodal Mass Spectrometry.

Surface-enhanced Raman scattering (SERS) is widely explored for the elucidation of underlying mechanisms behind biological processes. However, the capability of absolute quantitation of the number of nanoparticles from the SERS response remains a challenge. Here, we show for the first time the development of a new 2D quantitation model to allow calibration of the SERS response against the absolute concentration of SERS nanotags, as characterized by single particle inductively coupled plasma mass spectrometry (spICP-MS). A novel printing approach was adopted to prepare gelatin-based calibration standards containing the SERS nanotags, which consisted of gold nanoparticles and the Raman reporter 1,2-bis(4-pyridyl)ethylene. spICP-MS was used to characterize the Au mass concentration and particle number concentration of the SERS nanotags. Results from laser ablation inductively coupled plasma time-of-flight mass spectrometry imaging at a spatial resolution of 5 μm demonstrated a homogeneous distribution of the nanotags (between-line relative standard deviation < 14%) and a linear response of 197Au with increasing nanotag concentration (R2 = 0.99634) in the printed gelatin standards. The calibration standards were analyzed by SERS mapping, and different data processing approaches were evaluated. The reported calibration model was based on an "active-area" approach, classifying the pixels mapped as "active" or "inactive" and calibrating the SERS response against the total Au concentration and the particle number concentration, as characterized by spICP-MS. This novel calibration model demonstrates the potential for quantitative SERS imaging, with the capability of correlating the nanoparticle concentration to biological responses to further understand the underlying mechanisms of disease models.

Bioorthogonal surface-enhanced Raman scattering flower-like nanoprobe with embedded standards for accurate cancer cell imaging

Developing precise and effective strategies for cancer identification and imaging is attractive due to their importance for early cancer detection, prognosis, and subsequent treatment. Herein, we reported a novel bioorthogonal surface-enhanced Raman scattering (SERS) nanoprobe for accurate cancer cell imaging. A novel core-molecule-shell nanoflower (Au@4-MBN@Au) with rich electromagnetic hot spots and enhanced Raman scattering was first synthesized by optimizing the embedded concentrations of 4-mercaptobenzonitrile (4-MBN). Then, Au@4-MBN@Au was further modified with FA-PEG-SH molecules to acquire the bioorthogonal SERS nanoprobe Au@4-MBN@Au-PEG-FA. The SERS nanoprobe illustrated a robust and stable nitrile stretching vibration Raman signal (2223 cm−1) in the cellular silent region, ensuring high sensitivity and ultra-accuracy SERS imaging of cancer cells. Furthermore, cell imaging results demonstrated Au@4-MBN@Au-PEG-FA could recognize FR-positive HeLa cells with high selectivity due to the high affinity between folate receptor and folic acid. More notably, Au@4-MBN@Au-PEG-FA has been applied to identify FR-positive Hela cells from co-cultured cancer cells with similar morphology by SERS imaging for the first time. With improved signal-to-background ratio, high selectivity, and excellent stability, we anticipate the SERS nanoprobe Au@4-MBN@Au-PEG-FA could be applied for FR-related cancer theranostics and clinical detection in the future.

Design and Synthesis of SERS Materials for In Vivo Molecular Imaging and Biosensing.

Surface-enhanced Raman scattering (SERS) is a feasible and ultra-sensitive method for biomedical imaging and disease diagnosis. SERS is widely applied to in vivo imaging due to the development of functional nanoparticles encoded by Raman active molecules (SERS nanoprobes) and improvements in instruments. Herein, the recent developments in SERS active materials and their in vivo imaging and biosensing applications are overviewed. Various SERS substrates that have been successfully used for in vivo imaging are described. Then, the applications of SERS imaging in cancer detection and in vivo intraoperative guidance are summarized. The role of highly sensitive SERS biosensors in guiding the detection and prevention of diseases is discussed in detail. Moreover, its role in the identification and resection of microtumors and as a diagnostic and therapeutic platform is also reviewed. Finally, the progress and challenges associated with SERS active materials, equipment, and clinical translation are described. The present evidence suggests that SERS could be applied in clinical practice in the future.

A Multilayered Mesoporous Gold Nanoarchitecture for Ultraeffective Near-Infrared Light-Controlled Chemo/Photothermal Therapy for Cancer Guided by SERS Imaging.

Surface-enhanced Raman scattering (SERS) imaging has emerged as a promising tool for guided cancer diagnosis and synergistic therapies, such as combined chemotherapy and photothermal therapy (chemo-PTT). Yet, existing therapeutic agents often suffer from low SERS sensitivity, insufficient photothermal conversion, or/and limited drug loading capacity. Herein,a multifunctional theragnostic nanoplatform consisting of mesoporous silica-coated gold nanostar with a cyclic Arg-Gly-Asp (RGD)-coated gold nanocluster shell (named RGD-pAS@AuNC) is reported that exhibits multiple "hot spots" for pronouncedly enhanced SERS signals and improved near-infrared (NIR)-induced photothermal conversion efficiency (85.5%), with a large capacity for high doxorubicin (DOX) loading efficiency (34.1%, named RGD/DOX-pAS@AuNC) and effective NIR-triggered DOX release. This nanoplatform shows excellent performance in xenograft tumor model of HeLa cell targeting, negligible cytotoxicity, and good stability both in vitro and in vivo. By SERS imaging, the optimal temporal distribution of injected RGD/DOX-pAS@AuNCs at the tumor site is identified for NIR-triggered local chemo-PTT toward the tumor, achieving ultraeffective therapy in tumor cells and tumor-bearing mouse model with 5min of NIR irradiation (0.5Wcm-2 ). This work offers a promising approach to employing SERS imaging for effective noninvasive tumor treatment by on-site triggered chemo-PTT.

Facile synthesis of gold nanocages with silver nanocubes templates dual metal effects enabled SERS imaging and catalytic reduction.

Silver (Ag) nanomaterials featuring a cubic shape particularly represent supreme class of advance nanomaterials. This work explored a new precursor and its effect on morphological features of silver (Ag) nanocubes (NCs) serving as sacrificial templates for facile synthesis of gold NCs. The AgNCs were initially prepared utilizing sodium thiosulphate (Na2S2O3) as relatively stable S2- producing species along with a soft etchant source KCl. The effects of different potassium halides were evaluated to grasp control over seed mediated growth of Ag nanocubes. Taking the advantages of dual metallic properties, Ag@4MBA@AuNCs nanostructure was synthesized using 4-mercaptobenzoic acid (4MBA) as a Raman reporter molecule. This nanostructure showed 1010-times enhancement in surface enhanced Raman scattering (SERS) signal, leading to a highly sensitive imaging probe for the detection of even three breast cancer cells (MCF-7 cells) in vitro. Subsequently, the oxidative nanopeeling well accompanied by incorporation of Au/Ag alloy nanoparticles on AuNCs corona assembly was achieved, which facilitated the catalytic reduction of toxic nitrophenol to eco-friendly aminophenol. Such sophisticated and engineered nanoassemblies possess broad applications in bioanalysis.

Gap-enhanced gold nanodumbbells with single-particle surface-enhanced Raman scattering sensitivity.

Gap-enhanced Raman tags (GERTs) have been widely used for surface-enhanced Raman scattering (SERS) imaging due to their excellent SERS performances. Here, we reported a synthetic strategy for novel gap-enhanced dumbbell-like nanoparticles with anisotropic shell coatings. Controlled shell growth at the tips of gold nanorods was achieved by using cetyltrimethylammonium bromide (CTAB) as a capping agent. A mechanism related to the shape-directing effects of CTAB was proposed to explain the findings. Optimized gap-enhanced gold dumbbells exhibited highly enhanced SERS responses compared to rod cores, with an enhancement ratio of 101.5. We further demonstrated that gap-enhanced AuNDs exhibited single-particle SERS sensitivity with an acquisition time as fast as 0.1 s per spectrum, showing great potential for high-speed SERS imaging.

Evaluation of Surface-Enhanced Raman Scattering Substrate Consisting of Gold Nanoparticles Grown on Nanoarrays of Boehmite Fabricated using Magnetron Sputtering Process

A surface-enhanced Raman scattering (SERS) active structure allows the highly sensitive imaging of label-free molecular trace. A gold nanostructure with boehmite as a skeleton was fabricated by the inclined magnetron sputtering method. The characteristics of the prepared SERS imaging plate consisting of gold nanostructure on boehmite were evaluated as the follows. The distance dependence of the SERS intensity of 4,4′-bipyridine from the edge of the substrate indicated that the larger the SERS intensity becomes as the closer the distance approaches the substrate edged where the gold nanolayer was thicker. The trend of SERS dependence on distance was more pronounced at higher concentration of molecule and less pronounced at lower concentration. Using the SERS imaging plate will enable the further demonstration of ultrasenstive detection of chemical and biological molecules as environmental contaminants within a broad range of common fluidics for potential applications related to analytical chemistry and environmental monitoring.

Direct Modular Printing of Plasmonic Chemosensors

Here, we present and implement a new approach for producing modular inkjet-printable surface-enhanced Raman scattering (SERS) chemosensors. These sensors, combined with a rapid large field-of-view imaging system allow for fast imaging of the chemical characteristics of a sample. The performance of these materials is illustrated by printing a pH sensor on paper and interrogating aqueous solutions at different pH values. Results show single-shot images exceeding 9 mm2 which are readily read out via SERS imaging.