Self-Assembled Plasmonic Vesicles of SERS-Encoded Amphiphilic Gold Nanoparticles for Cancer Cell Targeting and Traceable Intracellular Drug Delivery

We report the development of bioconjugated plasmonic vesicles assembled from SERS-encoded amphiphilic gold nanoparticles for cancer-targeted drug delivery. This new type of plasmonic assemblies with a hollow cavity can play multifunctional roles as delivery carriers for anticancer drugs and SERS-active plasmonic imaging probes to specifically label targeted cancer cells and monitor intracellular drug delivery. We have shown that the pH-responsive disassembly of the plasmonic vesicle, stimulated by the hydrophobic-to-hydrophilic transition of the hydrophobic brushes in acidic intracellular compartments, allows for triggered intracellular drug release. Because self-assembled plasmonic vesicles exhibit significantly different plasmonic properties and greatly enhanced SERS intensity in comparison with single gold nanoparticles due to strong interparticle plasmonic coupling, disassembly of the vesicles in endocytic compartments leads to dramatic changes in scattering properties and SERS signals, which can serve as independent feedback mechanisms to signal cargo release from the vesicles. The unique structural and optical properties of the plasmonic vesicle have made it a promising platform for targeted combination therapy and theranostic applications by taking advantage of recent advances in gold nanostructure based in vivo bioimaging and photothermal therapy and their loading capacity for both hydrophilic (nucleic acids and proteins) and hydrophobic (small molecules) therapeutic agents.     

Intracellular SERS hybrid probes using BSA–reporter conjugates

Surface-enhanced Raman scattering (SERS) hybrid probes are characterized by the typical spectrum of a reporter molecule. In addition, they deliver information from their biological environment. Here, we report SERS hybrid probes generated by conjugating different reporter molecules to bovine serum albumin (BSA) and using gold nanoparticles as plasmonic core. Advantages of the BSA-conjugate hybrid nanoprobes over other SERS nanoprobes are a high biocompatibility, stabilization of the gold nanoparticles in the biological environment, stable reporter signals, and easy preparation. The coupling efficiencies of the BSA–reporter conjugates were determined by MALDI-TOF-MS. The conjugates’ characteristic SERS spectra differ from the spectra of unbound reporter molecules. This is a consequence of the covalent coupling, which leads to altered SERS enhancement and changes in the chemical structures of the reporter and of BSA. The application of the BSA–reporter conjugate hybrid probes in 3T3 cells, including duplex imaging, is demonstrated. Hierarchical cluster analysis and principal components analysis were applied for multivariate imaging using the SERS signatures of the incorporated SERS hybrid nanoprobes along with the spectral information from biomolecules in endosomal structures of cells. The results suggest more successful applications of the SERS hybrid probes in cellular imaging and other unordered high-density bioanalytical sensing.

Nanoparticle-mirror sandwich substrates for surface-enhanced Raman scattering

Sandwich surface-enhanced Raman scattering (SERS) substrates (3S) utilizing coupling between continuous metal films and plasmonic particles were fabricated using silver mirrors, electrochemically roughened films, and various sizes of silver nanoparticles. The effect of excitation wavelength and nanoparticle size on SERS spectra of poly(vinylpyridine), selected as a model compound, was studied to determine the optimum conditions for the strongest SERS signal. The Raman enhancement resulted from the plasmon coupling of silver nanoparticles to the underlying continuous film as well as the lateral plasmon coupling between the silver nanoparticles. The formation of the charge transfer complex was also observed. The 3S configuration was used to obtain SERS spectra of dipicolinic acid (DPA), a chemical signature for Bacillus anthracis.     

Controlled interparticle spacing for surface-modified gold nanoparticle aggregates

Aggregation of gold nanoparticles of increasing size has been studied as a consequence of adsorption of 2-aminothiophenol (ATP) on gold nanoparticle surfaces. The capping property of ATP in the acidic pH range has been accounted from UV-vis absorption spectroscopy and surface-enhanced Raman scattering (SERS) studies. The effect of nanoparticle size (8-55 nm) on the nature of aggregation as well as the variation in the optical response due to variable degree of interparticle coupling effects among the gold particles have been critically examined. Various techniques such as transmission electron microscopy, X-ray diffraction, zeta-potential, and average particle size measurement were undertaken to characterize the nanoparticle aggregates. The aggregate size, interparticle distances, and absorption band wavelengths were found to be highly dependent on the pH of the medium and the concentration of the capping agent, ATP. The acquired SERS spectra of ATP relate the interparticle spacing. It has been observed that the SERS signal intensities are different for different sized gold nanoparticles.     

Surface-enhanced Raman Scattering of Self-assembled Superstructures

Surface-enhanced Raman scattering(SERS) is a molecular specific spectroscopic technique that amplifies the Raman signal of absorbed molecules for up to 10¹⁰times. Over the past decades, SERS substrates experienced rapid growth, resulting in excellent development for SERS analysis. Because the surface plasmonic resonance coupling between individual materials can form a "hotspot" region to maximize the Raman signal, among many substrate construction strategies, self-assembly attracts more attention in constructing superstructures with strong, uniform and stable SERS activity. In addition, a number of plasmon-free nanomaterials with appropriate superstructures samely show enhanced SERS activity, which is primarily attributed to the formation of the optical resonator. This review aims to provide a scientific synopsis on the progress of self-assembled superstructures for SERS and ignite new dis˗ coveries in the SERS platform, as well as SERS applications in various fields.     

Surfactantless photochemical deposition of gold nanoparticles on an optical fiber core for surface-enhanced Raman scattering

Surface-enhanced Raman scattering (SERS) probes based on gold nanoparticles modifying the core of the optical fiber were made by a surfactantless photochemical deposition method. The growth kinetics and shape evolution of gold nanoparticles depending on different experimental conditions were studied. It was found that, under the condition of detectable gold nanoparticle deposition, increasing the concentration of chloroauric acid (HAuCl(4)) was not conducive to the deposition whereas increasing the concentration of sodium citrate (Na(3)Ct) would speed up the deposition. By controlling the concentration of the reaction solution and irradiation time, we obtained fused spherical-like, spherical, and flowerlike gold nanoparticles. To test the SERS activity of the probes, the SERS spectra of a rhodamine 6G aqueous solution were recorded in direct detection mode and remote mode. We have also developed a new approach to improving the SERS sensitivity when detecting in remote mode.     

Wide range temperature detection with hybrid nanoparticles traced by surface-enhanced Raman scattering

We report on the fabrication of a class of surface-enhanced Raman scattering(SERS)active thermometers,which consists of60 nm gold nanoparticles,encoded with Raman-active dyes,and a layer of thermoresponsive poly(N-isopropylacrylamide)(PNIPAM)brush with different chain lengths.These SERS-active nanoparticles can be optimized to maintain spectrally silent when staying as single particles in dispersion.Increasing temperature in a wide range from 25 to 55°C can reversibly induce the interparticle self-aggregation and turn on the SERS fingerprint signals with up to 58-fold of enhancement by taking advantage of the interparticle plasmonic coupling generated in the process of thermo-induced nanoparticles self-aggregation.Moreover,the most significative point is that these SERS probes could maintain their response to temperature and present all fingerprint signals in the presence of a colored complex.However,the UV-Vis spectra can distinguish the differences faintly and the solution color shows little change in such complex mixture.This proof-of-concept and Raman technique applied here allow for dynamic SERS platform for onsite temperature detection in a wide temperature range and offer unique advantages over other detection schemes.     

Single-molecule and single-nanoparticle SERS: from fundamental mechanisms to biomedical applications

This tutorial review discusses a new class of colloidal metal nanoparticles that is able to enhance the efficiencies of surface-enhanced Raman scattering (SERS) by as much as 10(14)-10(15) fold. This enormous enhancement allows spectroscopic detection and identification of single molecules located on the nanoparticle surface or at the junction of two particles under ambient conditions. Considerable progress has been made in understanding the enhancement mechanisms, including definitive evidence for the single-molecule origin of fluctuating SERS signals. For applications, SERS nanoparticle tags have been developed based on the use of embedded reporter molecules and a silica or polymer encapsulation layer. The SERS nanoparticle tags are capable of providing detailed spectroscopic information and are much brighter than semiconductor quantum dots in the near-infrared spectral window. These properties have raised new opportunities for multiplexed molecular diagnosis and in vivo Raman spectroscopy and imaging.     

Nanoparticle-based substrates for surface-enhanced Raman scattering detection of bacterial spores

The development of ultrasensitive and rapid methods for the detection of bacterial spores is important for medical diagnostics of infectious diseases. While Surface-Enhanced Raman Spectroscopic (SERS) techniques have been increasingly demonstrated for achieving this goal, a key challenge is the development of sensitive and stable SERS substrates or probes. This Minireview highlights recent progress in exploring metal nanoparticle-based substrates, especially gold nanoparticle-based substrates, for the detection of biomarkers released from bacterial spores. One recent example involves assemblies of gold nanoparticles on a gold substrate for the highly sensitive detection of dipicolinic acid (DPA), a biomarker for bacterial spores such as Bacillus anthracis. This type of substrate exploits a strong SERS effect produced by the particle-particle and particle-substrate plasmonic coupling. It is capable of accurate speciation of the biomarker but also selective detection under various reactive or non-reactive conditions. In the case of detecting Bacillus subtilis spores, the limit of detection is quite comparable (0.1 ppb for DPA, and 1.5 × 10(9) spores per L (or 2.5 × 10(-14) M)) with those obtained using silver nanoparticle-based substrates. Implications of the recent findings for improving the gold nanoparticle-based SERS substrates with ultrahigh sensitivity for the detection of bacterial spores are also discussed.     

Silver Coated Platinum Core–Shell Nanostructures on Etched Si Nanowires: Atomic Layer Deposition (ALD) Processing and Application in SERS

A new method to prepare plasmonically active noble metal nanostructures on large surface area silicon nanowires (SiNWs) mediated by atomic layer deposition (ALD) technology has successfully been demonstrated for applications of surface‐enhanced Raman spectroscopy (SERS)‐based sensing. As host material for the plasmonically active nanostructures we use dense single‐crystalline SiNWs with diameters of less than 100 nm as obtained by a wet chemical etching method based on silver nitrate and hydrofluoric acid solutions. The SERS active metal nanoparticles/islands are made from silver (Ag) shells as deposited by autometallography on the core nanoislands made from platinum (Pt) that can easily be deposited by ALD in the form of nanoislands covering the SiNW surfaces in a controlled way. The density of the plasmonically inactive Pt islands as well as the thickness of noble metal Ag shell are two key factors determining the magnitude of the SERS signal enhancement and sensitivity of detection. The optimized Ag coated Pt islands on SiNWs exhibit great potential for ultrasensitive molecular sensing in terms of high SERS signal enhancement ability, good stability and reproducibility. The plasmonic activity of the core‐shell Pt//Ag system that will be experimentally realized in this paper as an example was demonstrated in numerical finite element simulations as well as experimentally in Raman measurements of SERS activity of a highly diluted model dye molecule. The morphology and structure of the core‐shell Pt//Ag nanoparticles on SiNW surfaces were investigated by scanning‐ and transmission electron microscopy. Optimized core–shell nanoparticle geometries for maximum Raman signal enhancement is discussed essentially based on the finite element modeling.     

Self-assembled nanoparticle probes for recognition and detection of biomolecules

Colloidal gold nanocrystals have been used to develop a new class of nanobiosensors that is able to recognize and detect specific DNA sequences and single-base mutations in a homogeneous format. At the core of this biosensor is a 2.5-nm gold nanoparticle that functions as both a nano-scaffold and a nano-quencher (efficient energy acceptor). Attached to this core are oligonucleotide molecules labeled with a thiol group at one end and a fluorophore at the other. This hybrid bio/inorganic construct is found to spontaneously assemble into a constrained arch-like conformation on the particle surface. Binding of target molecules results in a conformational change, which restores the fluorescence of the quenched fluorophore. Unlike conventional molecular beacons with a stem-and-loop structure, the nanoparticle probes do not require a stem, and their background fluorescence increases little with temperature. In comparison with the organic quencher Dabcyl (4,4'-dimethylaminophenyl azo benzoic acid), metal nanoparticles have unique structural and optical properties for new applications in biosensing and molecular engineering.     

Block Copolymer Supported Gold Nanoparticles Assemblies with Exposed Gold Surface

Polymer-involved nanoparticles or nanoparticle assemblies are now facing a crossroad, where the exposure of nanoparticle and multiple nanoparticles cannot be obtained at the same time. Therefore, a new series of nanoparticle clusters is synthesized, where multiple gold nanoparticles assemble with amphiphilic block copolymers supporting inside. The exposure of gold nanoparticles of the structure is confirmed and increases the reduction rate of 4-nitrophenol by 60%. The assemblies can also be used as surface enhanced Raman scattering(SERS) probes with an enhancement factor(EF) as high as 3×10³.     

Raman Enhancement of Nanoparticle Dimers Self-Assembled Using DNA Origami Nanotriangles

Surface-enhanced Raman scattering is a powerful approach to detect molecules at very low concentrations, even up to the single-molecule level. One important aspect of the materials used in such a technique is how much the signal is intensified, quantified by the enhancement factor (EF). Herein we obtained the EFs for gold nanoparticle dimers of 60 and 80 nm diameter, respectively, self-assembled using DNA origami nanotriangles. Cy5 and TAMRA were used as surface-enhanced Raman scattering (SERS) probes, which enable the observation of individual nanoparticles and dimers. EF distributions are determined at four distinct wavelengths based on the measurements of around 1000 individual dimer structures. The obtained results show that the EFs for the dimeric assemblies follow a log-normal distribution and are in the range of 10⁶ at 633 nm and that the contribution of the molecular resonance effect to the EF is around 2, also showing that the plasmonic resonance is the main source of the observed signal. To support our studies, FDTD simulations of the nanoparticle’s electromagnetic field enhancement has been carried out, as well as calculations of the resonance Raman spectra of the dyes using DFT. We observe a very close agreement between the experimental EF distribution and the simulated values.     

An ionic surfactant-mediated Langmuir-Blodgett method to construct gold nanoparticle films for surface-enhanced Raman scattering

A gold nanoparticle film for surface-enhanced Raman scattering (SERS) was successfully constructed by an ionic surfactant-mediated Langmuir-Blodgett (LB) method. The gold film was formed by adding ethanol to a gold colloid/hexane mixture in the presence of dodecyltrimethylammonium bromide (DTAB). Consequently, gold nanoparticles (AuNPs) assembled at the water/hexane interface due to the decrease in surface charge density of AuNPs. Since DTAB binds the gold surface by a coulombic force, rather than a chemical bonding, it is easily replaced by target molecules for SERS purposes. The SERS enhancement factor of the 80 nm gold nanoparticle film was approximately 1.2 × 10(6) using crystal violet (CV) as a Raman dye. The SERS signal from the proposed DTAB-mediated film was approximately 10 times higher than that from the octanethiol-modified gold film, while the reproducibility and stability of this film compared to an octanethiol-modified film were similar. This method can also be applied to other metal nanostructures to fabricate metal films for use as a sensitive SERS substrate with a higher enhancement factor.     

Temperature-assisted ionic liquid dispersive liquid-liquid microextraction combined with high performance liquid chromatography for the determination of PCBs and PBDEs in water and urine samples

We report on silver–gold core-shell nanostructures that contain Methylene Blue (MB) at the gold–silver interface. They can be used as reporter molecules in surface-enhanced Raman scattering (SERS) labels. The labels are stable and have strong SERS activity. TEM imaging revealed that these nanoparticles display bright and dark stripe structures. In addition, these labels can act as probes that can be detected and imaged through the specific Raman signatures of the reporters. We show that such SERS probes can identify cellular structures due to enhanced Raman spectra of intrinsic cellular molecules measured in the local optical fields of the core-shell nanostructures. They also provide structural information on the cellular environment as demonstrated for these nanoparticles as new SERS-active and biocompatible substrates for imaging of live cells.

双金属双硅层核-壳纳米结构Au@SiO2@Ag@SiO2用于葡萄糖检测

制备了一种灵敏度高、 稳定性强的双金属双硅层核-壳结构纳米材料Au@SiO₂@Ag@SiO₂. 由于双金属之间的硅层促进了远程等离子体的激发转移, 使该纳米粒子具有良好的表面增强拉曼散射(SERS)的特性及优异的稳定性. 利用这种SERS活性材料能直接检测出人体尿液的主要成分, 且该材料呈现出对低浓度(10^-6 mol/L)葡萄糖的无标记高效检出能力. 此外, 还实现了人工尿液中等浓度(10^-3 mol/L)葡萄糖和尿素分子的同时检测, 以及实际尿液中10^-3 mol/L葡萄糖的检测. Au@SiO₂@Ag@SiO₂纳米粒子具有在多种生物分子存在时快速检测葡萄糖的实际应用潜力.     

Rolling‐Circle Amplification Detection of Thrombin Using Surface‐Enhanced Raman Spectroscopy with Core‐Shell Nanoparticle Probe

An ultrasensitive surface‐enhanced Raman spectroscopy (SERS) sensor based on rolling‐circle amplification (RCA)‐increased “hot‐spot” was developed for the detection of thrombin. The sensor contains a SERS gold nanoparticle@Raman label@SiO₂ core‐shell nanoparticle probe in which the Raman reporter molecules are sandwiched between a gold nanoparticle core and a thin silica shell by a layer‐by‐layer method. Thrombin aptamer sequences were immobilized onto the magnetic beads (MBs) through hybridization with their complementary strand. In the presence of thrombin, the aptamer sequence was released; this allowed the remaining single‐stranded DNA (ssDNA) to act as primer and initiate in situ RCA reaction to produce long ssDNAs. Then, a large number of SERS probes were attached on the long ssDNA templates, causing thousands of SERS probes to be involved in each biomolecular recognition event. This SERS method achieved the detection of thrombin in the range from 1.0×10^?12 to 1.0×10^?8 M and a detection limit of 4.2×10^?13 M , and showed good performance in real serum samples.     

Controlled Self-Assembly of Metallacycle-Bridged Gold Nanoparticles for Surface-Enhanced Raman Scattering

In this work, well-defined two-dimensional metallacycles have been successfully employed for the well-controlled self-assembly of gold nanoparticles (AuNPs) into discrete clusters such as dimers, trimers, tetramers, pentamers and even hexamers at the water–oil interface for the first time. Furthermore, the modular construction of metallacycle molecules allows precise control of spacing between the gold nanoparticles. Interestingly, it was found that interparticle spacing below 5 nm created by molecular metallacycles in the resultant discrete gold nanoparticle clusters led to a strong plasmon coupling, thus inducing great field enhancement inside the gap between the NPs. More importantly, different discrete clusters with precise interparticle spacing provide a well-defined system for studying the hot-spot phenomenon in surface-enhanced Raman scattering (SERS); this revealed that the SERS effects were closely related to the interparticle spacing.     

Surface-enhanced Raman scattering molecular sentinel nanoprobes for viral infection diagnostics

In this paper, we describe a surface-enhanced Raman scattering (SERS)-based detection approach, referred to as “molecular sentinel” (MS) plasmonic nanoprobes, to detect an RNA target related to viral infection. The MS method is essentially a label-free technique incorporating the SERS effect modulation scheme associated with silver nanoparticles and Raman dye-labeled DNA hairpin probes. Hybridization with target sequences opens the hairpin and spatially separates the Raman label from the silver surface thus reducing the SERS signal of the label. Herein, we have developed a MS nanoprobe to detect the human radical S-adenosyl methionine domain containing 2 (RSAD2) RNA target as a model system for method demonstration. The human RSAD2 gene has recently emerged as a novel host-response biomarker for diagnosis of respiratory infections. Our results showed that the RSAD2 MS nanoprobes exhibits high specificity and can detect as low as 1 nM target sequences. With the use of a portable Raman spectrometer and total RNA samples, we have also demonstrated for the first time the potential of the MS nanoprobe technology for detection of host-response RNA biomarkers for infectious disease diagnostics.     

Biosensors elaborated on gold nanoparticles, a PM-IRRAS characterisation of the IgG binding efficiency

This work is focused on studying the grafting of gold nanoparticles (Np) on a cystamine self-assembled monolayer on gold, in order to build sensitive immunosensors. The synthesis and deposition of gold nanoparticles, 13 and 55 nm sizes, were characterised by combining Polarisation Modulation Infrared Reflection-Absorption Spectroscopy (PM-IRRAS), X-ray Photoelectron Spectroscopy (XPS) Surface Enhanced Raman Scattering (SERS), and Atomic Force Microscopy (AFM) which all indicated the formation of a dispersed layer of nanoparticles. This observation is explained by the compromise between the high reactivity of amine-terminated layers towards gold, and interparticle repulsions. Nps were then functionalised with antibody probes, and the recognition by an anti-rIgG was assayed both on planar and Np gold surfaces.The important result is that nanoparticles of 55 nm are preferable for the following reasons: they enable to build a denser and well dispersed layer and they increase both the number of receptors (IgGs) and their accessibility. Beside these geometric improvements, a net enhancement of the Raman signal was observed on the 55 nm nanoparticle layer, making this new platform promising for optical detection based biosensors.