The discovery of the enhancement of Raman scattering by molecules adsorbed on nanostructured metal surfaces is a landmark in the history of spectroscopic and analytical techniques. Significant experimental and theoretical effort has been directed toward understanding the surface-enhanced Raman scattering (SERS) effect and demonstrating its potential in various types of ultrasensitive sensing applications in a wide variety of fields. In the 45 years since its discovery, SERS has blossomed into a rich area of research and technology, but additional efforts are still needed before it can be routinely used analytically and in commercial products. In this Review, prominent authors from around the world joined together to summarize the state of the art in understanding and using SERS and to predict what can be expected in the near future in terms of research, applications, and technological development. This Review is dedicated to SERS pioneer and our coauthor, the late Prof. Richard Van Duyne, whom we lost during the preparation of this article.

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Present and Future of Surface-Enhanced Raman Scattering

Extracellular vesicles (EVs) are a family of small membrane vesicles that carry information about cells by which they are secreted. Growing interest in the role of EVs in intercellular communication, but also in using their diagnostic, prognostic and therapeutic potential in (bio) medical applications, demands for accurate assessment of their biochemical and physical properties. In this review, we provide an overview of available technologies for EV analysis by describing their working principles, assessing their utility in EV research and summarising their potential and limitations. To emphasise the innovations in EV analysis, we also highlight the unique possibilities of emerging technologies with high potential for further development.

Extracellular Vesicle Quantification and Characterization: Common Methods and Emerging Approaches

The past decade has witnessed ongoing progress in precision medicine to improve human health. As an emerging diagnostic technique, liquid biopsy can provide real-time, comprehensive, dynamic physiological and pathological information in a noninvasive manner, opening a new window for precision medicine. Liquid biopsy depends on the sensitive and reliable detection of circulating targets (e.g., cells, extracellular vesicles, proteins, microRNAs) from body fluids, the performance of which is largely governed by recognition ligands. Aptamers are single-stranded functional oligonucleotides, capable of folding into unique tertiary structures to bind to their targets with superior specificity and affinity. Their mature evolution procedure, facile modification, and affinity regulation, as well as versatile structural design and engineering, make aptamers ideal recognition ligands for liquid biopsy. In this review, we present a broad overview of aptamer-based liquid biopsy techniques for precision medicine. We begin with recent advances in aptamer selection, followed by a summary of state-of-the-art strategies for multivalent aptamer assembly and aptamer interface modification. We will further describe aptamer-based micro-/nanoisolation platforms, aptamer-enabled release methods, and aptamer-assisted signal amplification and detection strategies. Finally, we present our perspectives regarding the opportunities and challenges of aptamer-based liquid biopsy for precision medicine.

Aptamer-Based Detection of Circulating Targets for Precision Medicine.

Direct quantification of cancerous exosomes via surface plasmon resonance with dual gold nanoparticle-assisted signal amplification.

Recent Advances in Biosensors for Detecting Cancer-Derived Exosomes

As a kind of most important cancer biomarker, exosomes are getting more frequently investigated in cancer diagnosis. In this study, we proposed an SERS-based method for the screening and simultaneous multiple detection of exosomes using magnetic substrates and SERS probes. Specifically, the capturing substrates are achieved using gold shell magnetic nanobeads modified by aptamers, which can capture most kinds of exosomes by recognizing the generic surface protein CD63. Moreover, the SERS probes are made of gold nanoparticles decorated with a Raman reporter and a specific aptamer for targeting exosomes. Further, for the simultaneous detection of multiple kinds of exosomes, three kinds of SERS probes were designed using different SERS reporters. While detecting specific kinds of exosomes, the capturing substrates were mixed with these three kinds of SERS probes. When the target exosome is present, an apta-immunocomplex can be formed among the target exosomes, the substrate, and the corresponding kind of SERS probes, and the other non-specific SERS probes remain in the suspension. Hence, an SERS signal with a decreased intensity will be detected in the supernatant, indicating the presence of the target exosomes. Finally, this detection method has also been successfully employed for the detection of exosomes in real blood samples; this proves that the proposed SERS-based method is a promising tool for clinical cancer screening based on exosomes.

Screening and multiple detection of cancer exosomes using an SERS-based method.

A novel kind of array-assisted surface-enhanced Raman spectroscopy (SERS) microfluidic chip (ArraySERS chip) is demonstrated for gas sensing, which has the advantages of both ultrahigh sensitivity and multiplex sensing ability. On the one hand, the introduction of a microstructured triangular array can greatly increase the multiple collision probability between gas molecules and sensing interfaces in the channel. Compared with traditional gas sensors using sealed boxes, where gaseous molecules move only by diffusion, the ArraySERS chip exhibits significantly improved sensitivity. On the other hand, a composite nanoparticle is fabricated as a SERS probe for reading out the fingerprint spectral data, which consists of metal-organic framework (MOF) materials [Zeolitic Imidazolate framework-8 (ZIF-8)] and Au@Ag nanocubes, as well as cysteamine (CA) that serves as the gas-capturing agent. The experimental results show that such a structure of the SERS probe can further increase the sensing ability because of better adsorption of ZIF-8 for gas and the lower SERS background of CA itself. In addition, the simultaneous detection of multiplex gases was easily performed according to their own intrinsic SERS signals. Taking aldehyde gas as a model of a typical air pollutant, trace and multicomponent detection was realized using the ArraySERS chip. The limit of detection value was as low as 1 ppb, which is 2 magnitudes lower than that obtained by traditional methods. This strategy can be well extended for the detection of universal gases and help unleash the potential of existing gas sensors, especially for samples at low concentrations in air.

Array-Assisted SERS Microfluidic Chips for Highly Sensitive and Multiplex Gas Sensing

Human mucin-1 (MUC1) has attracted considerable attention owing to its overexpression in diverse malignancies Here, for the rapid and efficient detection of MUC1, we present a SERS-colorimetric dual-mode aptasensor, by integrating SERS probes with magnetic separation, which has several distinctive advantages Using such a dual-mode aptasensor, the colorimetric functionality is distinguishable by the naked eye, providing a fast and straightforward screening ability for the detection of MUC1 Moreover, SERS-based detection greatly improves the detection sensitivity, reaching a limit of detection of 01 U/mL In addition, the combination of SERS and colorimetric method holds the advantages of these two techniques and thereby increases the reliability and efficiency of MUC1 detection On the one hand, the magnetic nanobeads functionalized with MUC1-specific aptamer were utilized as an efficient capturing substrate for separating MUC1 from biological complex medium On the other hand, the gold-silver core-shell nanoparticles modified with Raman reporters and the complementary sequences of MUC1 were used as the signal indicator, which could simultaneously report the SERS signal and colorimetric change This strategy can achieve a good detection range and realize MUC1 analysis in real patients’ samples Thus, we anticipate that this kind of aptasensor would provide promising potential applications in the diagnosis and prognosis of cancers

A SERS-colorimetric dual-mode aptasensor for the detection of cancer biomarker MUC1

Surface-enhanced Raman spectroscopy (SERS) is a promising technology for wearable sensors due to its fingerprint spectrum and high detection sensitivity. However, since SERS-activity is sensitive to both the distribution of "hotspots" and excitation angle, it is profoundly challenging to develop a wearable SERS sensor with high stability under various deformations during movements. Herein, inspired by omnidirectional light-harvesting of the compound eye of Xenos Peckii, a wearable SERS sensor is developed using omnidirectional plasmonic nanovoids array (OPNA), which is prepared by assembling a monolayer of metal nanoparticles into the artificial plasmonic compound-eye (APC). Specifically, APC is an interconnected frame containing omnidirectional "pockets" and acts as an "armour", not only rendering a broadband and omnidirectional enhancement of "hotspots" in the delicate nanoparticles array, but also maintaining an integrity of the "hotspots" against external mechanical deformations. Furthermore, an asymmetry super-hydrophilic pattern is fabricated on the surface of OPNA, endowing the hydrophobic OPNA with the ability to spontaneously extract and concentrate the analytes from sweat. Such an armored SERS sensor can enable the wearable and in situ analysis with high sensitivity and stability, exhibiting great potential in point-of-care analysis.

Wearable SERS Sensor Based on Omnidirectional Plasmonic Nanovoids Array with Ultra-High Sensitivity and Stability.

A surface-enhanced Raman scattering (SERS) aptasensor based on a hydrophobic assembled nanoacorn (HANA) was developed with improved reproducibility and reduced nonspecific binding effect. In the fabrication process, a hexagonal-packed gold film over nanosphere (AuFON) arrays was first obtained and used as a hydrophobic plasmonic substrate. Then, a uniform sub-3 nm molecular spacer array (containing Raman reporters) was prepared by patterning nanometric hydrophilic ultrathin patches onto the hydrophobic AuFON, in which the hydrophilic thin layer is composed of polymers and aptamers. During the sensing process, the HANA aptasensor smartly impedes the adsorption of SERS probes as Au@Ag nanocubes (Au@Ag NCs) in the absence of targets. In the presence of targets, the displacement of aptamers occurs due to the specific interaction between the targets and the aptamers, and the Au@Ag NCs can be assembled onto the hydrophilic patches on AuFON through electrostatic interactions with polymers. Thus, SERS signals of reporter molecules inside the spacer can be dramatically enhanced due to the formation of a nanoparticle-on-mirror (NPoM) array. In such a SERS aptasensor, the well-ordered distribution of SERS probes ensures excellent repeatability, while the precise subnanometer junctions guarantee high sensitivity. More importantly, since the hydrophobic surface can greatly reduce nonspecific adsorption, the tedious process of nonspecific blocking that is employed in traditional biosensors is no longer needed. Using such a SERS HANA platform, human epidermal growth factor receptor 2 (HER2) and three exosomal proteins were analyzed with high sensitivity and good reproducibility (RSD < 7%) in whole-blood samples.

Na Li

Papers

Screening and multiple detection of cancer exosomes using an SERS-based method.

Array-Assisted SERS Microfluidic Chips for Highly Sensitive and Multiplex Gas Sensing

A SERS-colorimetric dual-mode aptasensor for the detection of cancer biomarker MUC1

Wearable SERS Sensor Based on Omnidirectional Plasmonic Nanovoids Array with Ultra-High Sensitivity and Stability.

Hydrophobic Plasmonic Nanoacorn Array for a Label-Free and Uniform SERS-Based Biomolecular Assay.