Plasmonic gap nanostructures (PGNs) have been extensively investigated mainly because of their strongly enhanced optical responses, which stem from the high intensity of the localized field in the nanogap. The recently developed methods for the preparation of versatile nanogap structures open new avenues for the exploration of unprecedented optical properties and development of sensing applications relying on the amplification of various optical signals. However, the reproducible and controlled preparation of highly uniform plasmonic nanogaps and the prediction, understanding, and control of their optical properties, especially for nanogaps in the nanometer or sub-nanometer range, remain challenging. This is because subtle changes in the nanogap significantly affect the plasmonic response and are of paramount importance to the desired optical performance and further applications. Here, recent advances in the synthesis, assembly, and fabrication strategies, prediction and control of optical properties, and sensing applications of PGNs are discussed, and perspectives toward addressing these challenging issues and the future research directions are presented.

Synthesis, Assembly, Optical Properties, and Sensing Applications of Plasmonic Gap Nanostructures

Surface-enhanced Raman scattering (SERS) has emerged as a valuable technique for molecular identification. Due to the characteristics of high sensitivity, excellent signal specificity, and photobleaching resistance, SERS has been widely used in the fields of environmental monitoring, food safety, and disease diagnosis. By attaching the organic molecules to the surface of plasmonic nanoparticles, the obtained SERS tags show high-performance multiplexing capability for biosensing. The past decade has witnessed the progress of SERS tags for liquid biopsy, bioimaging, and theranostics applications. This review focuses on the advances of SERS tags in biomedical fields. We first introduce the building blocks of SERS tags, followed by the summarization of recent progress in SERS tags employed for detecting biomarkers, such as DNA, miRNA, and protein in biological fluids, as well as imaging from in vitro cell, bacteria, tissue to in vivo tumors. Further, we illustrate the appealing applications of SERS tags for delineating tumor margins and cancer diagnosis. In the end, perspectives of SERS tags projecting into the possible obstacles are deliberately proposed in future clinical translation.

SERS Tags for Biomedical Detection and Bioimaging

The lateral flow immunoassay (LFIA) has played a crucial role in early diagnosis during the current COVID-19 pandemic owing to its simplicity, speed and affordability for coronavirus antibody detection. However, the sensitivity of the commercially available LFIAs needs to be improved to better prevent the spread of the infection. Here, we developed an ultra-sensitive surface-enhanced Raman scattering-based lateral flow immunoassay (SERS-based LFIA) strip for simultaneous detection of anti-SARS-CoV-2 IgM and IgG by using gap-enhanced Raman nanotags (GERTs). The GERTs with a 1 nm gap between the core and shell were used to produce the “hot spots”, which provided about 30-fold enhancement as compared to conventional nanotags. The COVID-19 recombinant antigens were conjugated on GERTs surfaces and replaced the traditional colloidal gold for the Raman sensitive detection of human IgM and IgG. The LODs of IgM and IgG were found to be 1 ng/mL and 0.1 ng/mL (about 100 times decrease was observed as compared to commercially available LFIA strips), respectively. Moreover, under the condition of common nano-surface antigen, precise SERS signals proved the unreliability of quantitation because of the interference effect of IgM on IgG.

SERS-based lateral flow immunoassay for sensitive and simultaneous detection of anti-SARS-CoV-2 IgM and IgG antibodies by using gap-enhanced Raman nanotags.

Future precision medicine will be undoubtedly sustained by the detection of validated biomarkers that enable a precise classification of patients based on their predicted disease risk, prognosis, and response to a specific treatment. Up to now, genomics, transcriptomics, and immunohistochemistry have been the main clinically amenable tools at hand for identifying key diagnostic, prognostic, and predictive biomarkers. However, other molecular strategies, including metabolomics, are still in their infancy and require the development of new biomarker detection technologies, toward routine implementation into clinical diagnosis. In this context, surface-enhanced Raman scattering (SERS) spectroscopy has been recognized as a promising technology for clinical monitoring thanks to its high sensitivity and label-free operation, which should help accelerate the discovery of biomarkers and their corresponding screening in a simpler, faster, and less-expensive manner. Many studies have demonstrated the excellent performance of SERS in biomedical applications. However, such studies have also revealed several variables that should be considered for accurate SERS monitoring, in particular, when the signal is collected from biological sources (tissues, cells or biofluids). This Perspective is aimed at piecing together the puzzle of SERS in biomarker monitoring, with a view on future challenges and implications. We address the most relevant requirements of plasmonic substrates for biomedical applications, as well as the implementation of tools from artificial intelligence or biotechnology to guide the development of highly versatile sensors.

https://zenodo.org/record/6651711/files/2022%20Plou%20acsphotonics.pdf

Prospects of Surface-Enhanced Raman Spectroscopy for Biomarker Monitoring toward Precision Medicine

Surface-enhanced Raman scattering (SERS) technique has shown extraordinary features for biomedical applications. The implementation of SERS nanotags has opened a new era for bioimaging and detections. As a powerful tool, SERS nanotags provide favorable properties such as fingerprint spectrum, narrow peak linewidth, good photostability, and high spatial resolution accompanied by various rational designs of nanoparticles. They have proven as useful imaging agents for in vivo, ex vivo, and in vitro detection of cancerous cells and tissues. This tutorial provides the basic principles of SERS and SERS nanotags, including recent progress of SERS-based bioimaging applications, as well as the outlooks into the future developments toward practical clinical SERS.

Surface-enhanced Raman scattering nanotags for bioimaging

Surface-enhanced Raman scattering (SERS) nanotags are widely used in the biomedical field including live-cell imaging due to the high specificity from their fingerprint spectrum and the multiplexing capability from the ultra-narrow linewidth. However, long-term live-cell Raman imaging is limited due to the photodamage from a relatively long exposure time and a high laser power, which are needed for acquiring detectable Raman signals. In this work, we attempt to resolve this issue by developing ultrabright gap-enhanced resonance Raman tags (GERRTs), consisting of a petal-like gold core and a silver shell with the near-infrared resonant reporter of IR-780 embedded in between, for long-term and high-speed live-cell imaging. GERRTs exhibit an ultrahigh Raman intensity down to a single-nanoparticle level in aqueous solution and the solid state upon 785 nm excitation, allowing for high-resolution time-lapse live-cell Raman imaging with an exposure time of 1 ms per pixel and a laser power of 50 μW. Under these measurement conditions, we can possibly capture dynamic cellular processes with a high temporal resolution, and track living cells for long periods of time owing to the reduced photodamage to cells. These nanotags open new opportunities for ultrasensitive, low-phototoxic, and long-term live-cell imaging.

Gap-enhanced resonance Raman tags for live-cell imaging

Single-molecule (SM) detection in surface-enhanced Raman spectroscopy (SERS) demonstrates ultra-high sensitivity and boosts wide applications Bi-analyte SERS (BiASERS) technique largely improves t

Ag-Coated Au Nanopetals: Dual-Type Single-Nanoparticle Detection of Gap-Enhanced Resonance Raman Tags

Raman‐fluorescence dual‐mode enhanced nanoparticles have enormous potential for bioimaging with combined advantages of sensitivity and speed. This is primarily achieved through a trade‐off between fluorescence quenching and electromagnetic (EM) enhancement on the plasmonic metal surface, as demonstrated in previous research. A strategy that can minimize EM‐field attenuation and temporal photobleaching would be highly desirable. In this study, a novel approach using Raman‐fluorescence enhanced dual‐mode nanoparticles with the near‐infrared fluorescence reporter IR780 directly embedded in the ultra‐high EM fields between gold (Au) nanopetals of various morphology and a silver (Ag) coating without a spacer is presented. The results show these nanoparticles to be single‐nanoparticle Raman sensitive and that they can generate a fluorescence enhancement factor as high as 1113 experimentally and 2000 by numerical simulation. The random morphology of the nanopetals supports broadband resonances for both fluorescence excitation and emission, resulting in nanowatt detectability, the dual‐mode photostability of more than 30 min under continuous laser irradiation, and a long shelf life, making them promising for wide applications in bioimaging with ultra‐brightness, low laser power, and long‐duration monitoring. In summary, they represent a novel strategy for high‐performance Raman‐fluorescence enhancement dual‐mode nanotags.

Xinyuan Bi

Papers

Surface-enhanced Raman scattering nanotags for bioimaging

Gap-enhanced resonance Raman tags for live-cell imaging

Ag-Coated Au Nanopetals: Dual-Type Single-Nanoparticle Detection of Gap-Enhanced Resonance Raman Tags

Ultrahigh Raman‐Fluorescence Dual‐Enhancement in Nanogaps of Silver‐Coated Gold Nanopetals

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