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.

We fabricated a highly oxidized large-scale graphene platform using chemical vapor deposition (CVD) and UV/ozone-based oxidation methods. This platform offers a large-scale surface-enhanced Raman scattering (SERS) substrate with large chemical enhancement in SERS and reproducible SERS signals over a centimeter-scale graphene surface. After UV-induced ozone generation, ozone molecules were reacted with graphene to produce oxygen-containing groups on graphene and induced the p-type doping of the graphene. These modifications introduced the structural disorder and defects on the graphene surface and resulted in a large chemical mechanism-based signal enhancement from Raman dye molecules [rhodamine B (RhB), rhodamine 6G (R6G), and crystal violet (CV) in this case] on graphene. Importantly, the enhancement factors were increased from ∼10(3) before ozone treatment to ∼10(4), which is the largest chemical enhancement factor ever on graphene, after 5 min ozone treatment due to both high oxidation and p-doping effects on graphene surface. Over a centimeter-scale area of this UV/ozone-oxidized graphene substrate, strong SERS signals were repeatedly and reproducibly detected. In a UV/ozone-based micropattern, UV/ozone-treated areas were highly Raman-active while nontreated areas displayed very weak Raman signals.

Plasmonic coupling-based electromagnetic field localization and enhancement are becoming increasingly important in chemistry, nanoscience, materials science, physics, and engineering over the past decade, generating a number of new concepts and applications. Among the plasmonically coupled nanostructures, metal nanostructures with nanogaps have been of special interest due to their ultrastrong electromagnetic fields and controllable optical properties that can be useful for a variety of signal enhancements such as surface-enhanced Raman scattering (SERS). The Raman scattering process is highly inefficient, with a very small cross-section, and Raman signals are often poorly reproducible, meaning that very strong, controllable SERS is needed to obtain reliable Raman signals with metallic nanostructures and thus open up new avenues for a variety of Raman-based applications. More specifically, plasmonically coupled metallic nanostructures with ultrasmall (∼1 nm or smaller) nanogaps can generate very strong and tunable electromagnetic fields that can generate strong SERS signals from Raman dyes in the gap, and plasmonic nanogap-enhanced Raman scattering can be defined as Raman signal enhancement from plasmonic nanogap particles with ∼1 nm gaps. However, these promising nanostructures with extraordinarily strong optical signals have shown limited use for practical applications, largely due to the lack of design principles, high-yield synthetic strategies with nanometer-level structural control and reproducibility, and systematic, reliable single-molecule/single-particle-level studies on their optical properties. All these are extremely important challenges because even small changes (<1 nm) in the structure of the coupled plasmonic nanogaps can significantly affect the plasmon mode and signal intensity. In this Account, we examine and summarize recent breakthroughs and advances in plasmonic nanogap-enhanced Raman scattering with metal nanogap particles with respect to the design and synthesis of plasmonic nanogap structures, as well as ultrasensitive and quantitative Raman signal detection using these structures. The applications and prospects of plasmonic nanogap particle-based SERS are also discussed. In particular, reliable synthetic and measurement strategies for plasmonically coupled nanostructures with ∼1 nm gap, in which both the nanogap size and the position of a Raman-active molecule in the gap can be controlled with nanometer/sub-nanometer-level precision, can address important issues regarding the synthesis and optical properties of plasmonic nanostructures, including structural and signal reproducibility. Further, single-molecule/single-particle-level studies on the plasmonic properties of these nanogap structures revealed that these particles can generate ultrastrong, quantifiable Raman signals in a highly reproducible manner.

Recent advances of plasmonic nanoparticles include fascinating developments in the fields of energy, catalyst chemistry, optics, biotechnology, and medicine. The plasmonic photothermal properties of metallic nanoparticles are of enormous interest in biomedical fields because of their strong and tunable optical response and the capability to manipulate the photothermal effect by an external light source. To date, most biomedical applications using photothermal nanoparticles have focused on photothermal therapy; however, to fully realize the potential of these particles for clinical and other applications, the fundamental properties of photothermal nanoparticles need to be better understood and controlled, and the photothermal effect‐based diagnosis, treatment, and theranostics should be thoroughly explored. This Progress Report summarizes recent advances in the understanding and applications of plasmonic photothermal nanoparticles, particularly for sensing, imaging, therapy, and drug delivery, and discusses the future directions of these fields.

Plasmonic nanostructures possessing unique and versatile optoelectronic properties have been vastly investigated over the past decade. However, the full potential of plasmonic nanostructure has not yet been fully exploited, particularly with single-component homogeneous structures with monotonic properties, and the addition of new components for making multicomponent nanoparticles may lead to new-yet-unexpected or improved properties. Here we define the term “multi-component nanoparticles” as hybrid structures composed of two or more condensed nanoscale domains with distinctive material compositions, shapes, or sizes. We reviewed and discussed the designing principles and synthetic strategies to efficiently combine multiple components to form hybrid nanoparticles with a new or improved plasmonic functionality. In particular, it has been quite challenging to precisely synthesize widely diverse multicomponent plasmonic structures, limiting realization of the full potential of plasmonic heterostructures. To address this challenge, several synthetic approaches have been reported to form a variety of different multicomponent plasmonic nanoparticles, mainly based on heterogeneous nucleation, atomic replacements, adsorption on supports, and biomolecule-mediated assemblies. In addition, the unique and synergistic features of multicomponent plasmonic nanoparticles, such as combination of pristine material properties, finely tuned plasmon resonance and coupling, enhanced light-matter interactions, geometry-induced polarization, and plasmon-induced energy and charge transfer across the heterointerface, were reported. In this review, we comprehensively summarize the latest advances on state-of-art synthetic strategies, unique properties, and promising applications of multicomponent plasmonic nanoparticles. These plasmonic nanoparticles including heterostructured nanoparticles and composite nanostructures are prepared by direct synthesis and physical force- or biomolecule-mediated assembly, which hold tremendous potential for plasmon-mediated energy transfer, magnetic plasmonics, metamolecules, and nanobiotechnology.

Synthesizing plasmonic nanostructures in an ultraprecise manner is of paramount importance because the nanometer-scale structural details can significantly affect their plasmonic properties. Au nanocubes (AuNCs) have been a highly promising, heavily studied nanostructure with high potential in various fields, but an ultraprecise synthesis from 10 to 100 nm in size over a large number of AuNCs has not been well established. Precisely structured AuNC-based studies for a highly reproducible, quantitative plasmonic signal generation [e.g., quantitative surface-enhanced Raman scattering (SERS)] are needed for reliable use and exploration in the beneficial properties of AuNCs. Here, we developed a strategy for AuNC synthesis with the desired size and shape, ranging from 17 to 78 nm particularly with highly controlled corner sharpness, by precisely controlling the growth rate of different facets and AuNC-specific flocculation which enabled ultrahigh yields (∼98-99%). Importantly, the precisely shaped AuNCs can scatter light in a spectrally reproducible manner, and the SERS enhancement factors (EFs) for the AuNC dimers are very narrowly distributed (the EFs of 72 nm sharp-cornered cube dimers have a distribution within 1 order of magnitude). Our results pave the paths to ultrahigh yield synthesis of metal nanocubes with a precise size and shape and offer single-particle-level spectral controllability and reproducibility over a large number of particles.

Single-molecule fluorescence spectroscopy has proven to be instrumental in understanding a wide range of biological phenomena at the nanoscale. Important examples of what this technique can yield to biological sciences are the mechanistic insights on protein-protein and protein-nucleic acid interactions. When interactions of proteins are probed at the single-molecule level, the proteins or their substrates are often immobilized on a glass surface, which allows for a long-term observation. This immobilization scheme may introduce unwanted surface artifacts. Therefore, it is essential to passivate the glass surface to make it inert. Surface coating using polyethylene glycol (PEG) stands out for its high performance in preventing proteins from non-specifically interacting with a glass surface. However, the polymer coating procedure is difficult, due to the complication arising from a series of surface treatments and the stringent requirement that a surface needs to be free of any fluorescent molecules at the end of the procedure. Here, we provide a robust protocol with step-by-step instructions. It covers surface cleaning including piranha etching, surface functionalization with amine groups, and finally PEG coating. To obtain a high density of a PEG layer, we introduce a new strategy of treating the surface with PEG molecules over two rounds, which remarkably improves the quality of passivation. We provide representative results as well as practical advice for each critical step so that anyone can achieve the high quality surface passivation.

By utilizing oligonucleotide-modified Au nanoparticles encoded with sequences that act as biobarcodes, one can screen for multiple target polyvalent proteins simultaneously in one solution. This novel concept was demonstrated with two types of detection formats, a homogeneous assay and one based on oligonucleotide microarrays. With such an approach, one can prepare an extraordinarily large number of barcodes from synthetically accessible oligonucleotides (e.g., a 12-mer sequence offers 4(12) possible barcodes).