High‐Performance SERS Substrate Based on Hierarchical 3D Cu Nanocrystals with Efficient Morphology Control

Cu nanocrystals of various shapes are synthesized via a universal, eco‐friendly, and facile colloidal method on Al substrates using hexadecylamine (HDA) as a capping agent and glucose as a reductant. By tuning the concentration of the capping agent, hierarchical 3D Cu nanocrystals show pronounced surface‐enhanced Raman scattering (SERS) through the concentrated hot spots at the sharp tips and gaps due to the unique 3D structure and the resulting plasmonic couplings. Intriguingly, 3D sword‐shaped Cu crystals have the highest enhancement factor (EF) because of their relatively uniform size distribution and alignment. This work opens new pathways for efficiently realizing morphology control for Cu nanocrystals as highly efficient SERS platforms.     

A SERS‐Assisted 3D Barcode Chip for High‐Throughput Biosensing

A surface enhanced Raman scattering (SERS)‐assisted 3D barcode chip has been developed for high‐throughput biosensing. The 3D barcode is realized through joint 2D spatial encoding with the Raman spectroscopic encoding, which stores the SERS fingerprint information in the format of a 2D array. Here, the concept of SERS‐assisted 3D barcode is demonstrated through multiplex immunoassay, where simultaneous detection of multiple targets in different samples has been achieved using a microfluidic platform. First, multiple proteins in different samples are spatially separated using a microfluidic patterned antibody barcode substrate, forming a 2D hybridization array. Then the SERS probes are used to identify and quantify the proteins. As different SERS probes are labeled with different Raman reporters, they could be employed as “SERS tags” to incorporate spectroscopic information into the 3D barcode. In this 3D barcode, the 2D spatial information helps to differentiate the samples and targets while the SERS information allows quantitative multiplex detection. It is found that the SERS‐assisted 3D barcode chip can not only accomplish one‐step multiplex detection within 30 min but also achieve an ultrasensitivity down to 10 fg mL^?1 (≈70 aM), which is expected to provide a promising tool for high‐throughput biomedical applications.     

Ag Nanoparticle‐Grafted PAN‐Nanohump Array Films with 3D High‐Density Hot Spots as Flexible and Reliable SERS Substrates

A facile fabrication approach of large‐scale flexible films is reported, with one surface side consisting of Ag‐nanoparticle (Ag‐NP) decorated polyacrylonitrile (PAN) nanohump (denoted as Ag‐NPs@PAN‐nanohump) arrays. This is achieved via molding PAN films with ordered nanohump arrays on one side and then sputtering much smaller Ag‐NPs onto each of the PAN‐nanohumps. Surface‐enhanced Raman scattering (SERS) activity of the Ag‐NPs@PAN‐nanohump array films can be improved by curving the flexible PAN film with ordered nanohump arrays during the Ag‐sputtering process to increase the density of the Ag‐NPs on the sidewalls of the PAN‐nanohumps. More 3D hot spots are thus achieved on a large‐scale. The Ag‐NPs@PAN‐nanohump array films show high SERS activity with good Raman signal reproducibility for Rhodamine 6G probe molecules. To trial their practical application, the Ag‐NPs@PAN‐nanohump array films are employed as SERS substrates for trace detection of trinitrotoluene and a congener of polychlorinated biphenyls. A lower detection limit of 10⁻¹²m and 10⁻⁵m can be achieved, respectively. Furthermore, the flexible Ag‐NPs@PAN‐nanohump array films can also be utilized as swabs to probe traces of methyl parathion on the surface of fruits such as apples. The as‐fabricated SERS substrates therefore have promising potential for applications in rapid safety inspection and environmental protection.     

M‐shaped Grating by Nanoimprinting: A Replicable,Large‐Area,Highly Active Plasmonic Surface‐Enhanced Raman Scattering Substrate with Nanogaps

Plasmonic nanostructures separated by nanogaps enable strong electromagnetic‐field confinement on the nanoscale for enhancing light‐matter interactions, which are in great demand in many applications such as surface‐enhanced Raman scattering (SERS). A simple M‐shaped nanograting with narrow V‐shaped grooves is proposed. Both theoretical and experimental studies reveal that the electromagnetic field on the surface of the M grating can be pronouncedly enhanced over that of a grating without such grooves, due to field localization in the nanogaps formed by the narrow V grooves. A technique based on room‐temperature nanoimprinting lithography and anisotropic reactive‐ion etching is developed to fabricate this device, which is cost‐effective, reliable, and suitable for fabricating large‐area nanostructures. As a demonstration of the potential application of this device, the M grating is used as a SERS substrate for probing Rhodamine 6G molecules. Experimentally, an average SERS enhancement factor as high as 5×10⁸ has been achieved, which verifies the greatly enhanced light–matter interaction on the surface of the M grating over that of traditional SERS surfaces.     

Multifunctional Silver‐Embedded Magnetic Nanoparticles as SERS Nanoprobes and Their Applications

In this study, surface‐enhanced Raman spectroscopy (SERS)‐encoded magnetic nanoparticles (NPs) are prepared and utilized as a multifunctional tagging material for cancer‐cell targeting and separation. First, silver‐embedded magnetic NPs are prepared, composed of an 18‐nm magnetic core and a 16‐nm‐thick silica shell with silver NPs formed on the surface. After simple aromatic compounds are adsorbed on the silver‐embedded magnetic NPs, they are coated with silica to provide them with chemical and physical stability. The resulting silica‐encapsulated magnetic NPs (M‐SERS dots) produce strong SERS signals and have magnetic properties. In a model application as a tagging material, the M‐SERS dots are successfully utilized for targeting breast‐cancer cells (SKBR3) and floating leukemia cells (SP2/O). The targeted cancer cells can be easily separated from the untargeted cells using an external magnetic field. The separated targeted cancer cells exhibit a Raman signal originating from the M‐SERS dots. This system proves to be an efficient tool for separating targeted cells. Additionally, the magnetic‐field‐induced hot spots, which can provide a 1000‐times‐stronger SERS intensity due to aggregation of the NPs, are studied.     

Uniform Microgels Containing Agglomerates of Silver Nanocubes for Molecular Size‐Selectivity and High SERS Activity

Surface‐enhanced Raman scattering (SERS) is a promising technique for molecular analysis as the molecular fingerprints (Raman spectra) are amplified to detectable levels compared with common spectroscopy. Metal nanostructures localize electromagnetic field on their surfaces, which can lead to dramatic increase of Raman intensity of molecules adsorbed. However, the metal surfaces are prone to contamination, thereby requiring pretreatment of samples to remove adhesive molecules. To avoid the pretreatment and potentially achieve point‐of‐care (POC) analysis, we have developed SERS‐active microgels using the droplet‐microfluidic system. As the microgels are composed of water‐swollen network with consistent mesh size, they selectively allow diffusion of molecules smaller than the mesh, thereby excluding large adhesives. To render the microgels highly SERS‐active, we destabilize silver nanocubes to form agglomerates, which are embedded in the matrix of microgels. The nanogaps in the agglomerates provide high sensitivity in Raman measurement and size‐selective permeability of the microgel matrix obviates the pretreatment of samples. To validate the functions, we demonstrate the direct detection of Aspirin dissolved in whole blood without any pretreatment.     

In Situ Two‐Step Photoreduced SERS Materials for On‐Chip Single‐Molecule Spectroscopy with High Reproducibility

A method is developed to synthesize surface‐enhanced Raman scattering (SERS) materials capable of single‐molecule detection, integrated with a microfluidic system. Using a focused laser, silver nanoparticle aggregates as SERS monitors are fabricated in a microfluidic channel through photochemical reduction. After washing out the monitor, the aggregates are irradiated again by the same laser. This key step leads to full reduction of the residual reactants, which generates numerous small silver nanoparticles on the former nanoaggregates. Consequently, the enhancement ability of the SERS monitor is greatly boosted due to the emergence of new “hot spots.” At the same time, the influence of the notorious “memory effect” in microfluidics is substantially suppressed due to the depletion of surface residues. Taking these advantages, two‐step photoreduced SERS materials are able to detect different types of molecules with the concentration down to 10^?13m . Based on a well‐accepted bianalyte approach, it is proved that the detection limit reaches the single‐molecule level. From a practical point of view, the detection reproducibility at different probing concentrations is also investigated. It is found that the effective single‐molecule SERS measurements can be raised up to ≈50%. This microfluidic SERS with high reproducibility and ultrasensitivity will find promising applications in on‐chip single‐molecule spectroscopy.     

Split‐GFP: SERS Enhancers in Plasmonic Nanocluster Probes

The assembly of plasmonic metal nanoparticles into hot spot surface‐enhanced Raman scattering (SERS) nanocluster probes is a powerful, yet challenging approach for ultrasensitive biosensing. Scaffolding strategies based on self‐complementary peptides and proteins are of increasing interest for these assemblies, but the electronic and the photonic properties of such hybrid nanoclusters remain difficult to predict and optimize. Here, split‐green fluorescence protein (sGFP) fragments are used as molecular glue and the GFP chromophore is used as a Raman reporter to assemble a variety of gold nanoparticle (AuNP) clusters and explore their plasmonic properties by numerical modeling. It is shown that GFP seeding of plasmonic nanogaps in AuNP/GFP hybrid nanoclusters increases near‐field dipolar couplings between AuNPs and provides SERS enhancement factors above 10⁸. Among the different nanoclusters studied, AuNP/GFP chains allow near‐infrared SERS detection of the GFP chromophore imidazolinone/exocyclic C?C vibrational mode with theoretical enhancement factors of 10⁸–10⁹. For larger AuNP/GFP assemblies, the presence of non‐GFP seeded nanogaps between tightly packed nanoparticles reduces near‐field enhancements at Raman active hot spots, indicating that excessive clustering can decrease SERS amplifications. This study provides rationales to optimize the controlled assembly of hot spot SERS nanoprobes for remote biosensing using Raman reporters that act as molecular glue between plasmonic nanoparticles.     

A High‐Sensitivity and Low‐Power Theranostic Nanosystem for Cell SERS Imaging and Selectively Photothermal Therapy Using Anti‐EGFR‐Conjugated Reduced Graphene Oxide/Mesoporous Silica/AuNPs Nanosheets

A high‐sensitivity and low‐power theranostic nanosystem that combines with synergistic photothermal therapy and surface‐enhanced Raman scattering (SERS) mapping is constructed by mesoporous silica self‐assembly on the reduced graphene oxide (rGO) nanosheets with nanogap‐aligned gold nanoparticles (AuNPs) encapsulated and arranged inside the nanochannels of the mesoporous silica layer. Rhodamine 6G (R6G) as a Raman reporter is then encapsulated into the nanochannels and anti‐epidermal growth factor receptor (EGFR) is conjugated on the nanocomposite surface, defined as anti‐EGFR‐PEG‐rGO@CPSS‐Au‐R6G, where PEG is polyethylene glycol and CPSS is carbon porous silica nanosheets. SERS spectra results show that rGO@CPSS‐Au‐R6G enhances 5 × 10⁶ magnification of the Raman signals and thus can be applied in the noninvasive cell tracking. Furthermore, it displays high sensitivity (detection limits: 10^?8m R6G solution) due to the “hot spots” effects by the arrangements of AuNPs in the nanochannels of mesoporous silica. The highly selective targeting of overexpressing EGFR lung cancer cells (A549) is observed in the anti‐EGFR‐PEG‐rGO@CPSS‐Au‐R6G, in contrast to normal cells (MRC‐5). High photothermal therapy efficiency with a low power density (0.5 W cm^?2) of near‐infrared laser can be achieved because of the synergistic effect by conjugated AuNPs and rGO nanosheets. These results demonstrate that the anti‐EGFR‐PEG‐rGO@CPSS‐Au‐R6G is an excellent new theranostic nanosystem with cell targeting, cell tracking, and photothermal therapy capabilities.