Electrostatic tweezer for droplet manipulation.

Various physical tweezers for manipulating liquid droplets based on optical, electrical, magnetic, acoustic, or other external fields have emerged and revolutionized research and application in medical, biological, and environmental fields. Despite notable progress, the existing modalities for droplet control and manipulation are still limited by the extra responsive additives and relatively poor controllability in terms of droplet motion behaviors, such as distance, velocity, and direction. Herein, we report a versatile droplet electrostatic tweezer (DEST) for remotely and programmatically trapping or guiding the liquid droplets under diverse conditions, such as in open and closed spaces and on flat and tilted surfaces as well as in oil medium. DEST, leveraging on the coulomb attraction force resulting from its electrostatic induction to a droplet, could manipulate droplets of various compositions, volumes, and arrays on various substrates, offering a potential platform for a series of applications, such as high-throughput surface-enhanced Raman spectroscopy detection with single measuring time less than 20 s.

Wearable Hydrogel SERS Chip Utilizing Plasmonic Trimers for Uric Acid Analysis in Sweat.

Uric acid is typically measured through blood tests, which can be inconvenient and uncomfortable for patients. Herein, we propose a wearable surface-enhanced Raman scattering (SERS) chip, incorporating a hydrogel membrane with integrated plasmonic trimers, for noninvasive monitoring of uric acid in sweat. The plasmonic trimers feature sub 5 nm nanogaps, generating strong electromagnetic fields to boost the Raman signal of surrounding molecules. Simultaneously, the hydrogel membrane pumps sweat through these gaps, efficiently capturing sweat biomarkers for SERS detection. The chip can achieve saturation adsorption of sweat within 5 min, eliminating variations in individual sweat production rates. Dynamic SERS tracking of uric acid and lactic acid levels during anaerobic exercise reveals a temporary suppression of uric acid metabolism, likely due to metabolic competition with lactic acid. Furthermore, long-term monitoring correlates well with blood test results, confirming that regular exercise helps reduce serum uric acid levels and supporting its potential in managing hyperuricemia.

A Statistical Route to Robust SERS Quantitation Beyond the Single-Molecule Level.

Single-molecule surface-enhanced Raman spectroscopy (SM-SERS) holds great potential to revolutionize ultratrace quantitative analysis. However, achieving quantitative SM-SERS is challenging because of strong intensity fluctuation and blinking characteristics. In this study, we reveal the relation P = 1 - e-α between the statistical SERS probability P and the microscopic average molecule number α in SERS spectra, which lays the physical foundation for a statistical route to implement SM-SERS quantitation. Utilizing SERS probability calibration, we achieve quantitative SERS analysis with batch-to-batch robustness, extremely wide detection range of concentration covering 9 orders of magnitude, and ultralow detection limit far below the single-molecule level. These results indicate the physical feasibility of robust SERS quantitation through statistical route and certainly open a new avenue for implementing SERS as a practical analysis tool in various application scenarios.

Re-understanding of SERS for General and Standardized Quantitative Analysis.

We proposed two physical concepts, i.e., an intramolecular relative cross section (RCS) and an intermolecular relative scattering ability (RSA), to re-understand and re-describe surface-enhanced Raman scattering (SERS) and established a general SERS quantification theory. Interestingly, RCS and RSA are intrinsic factors and are experimentally measurable to form datasheets of molecules, namely, SERS cards, with which a standard SERS quantification procedure was established. The validity of the theory and quantification procedure was confirmed by experiments. Surprisingly, RCS and RSA are also valid for complex systems being considered as virtual molecules and are experimentally measurable. This simplifies complex systems into analyte-virtual molecule binary systems. With this consideration, trace-level mitoxantrone (a typical cancer drug metabolite) in artificial urine was accurately predicted. The theory, the SERS cards, the standard quantification procedure, and the virtual molecule concept pave a way toward quantitative and standardized SERS spectroscopy in dealing with real-world problems and complex samples.

Immobilization of Membrane-Associated Protein Complexes on SERS-Active Nanomaterials for Structural and Dynamic Characterization.

Exploring the structural basis of membrane proteins is significant for a deeper understanding of protein functions. In situ analysis of membrane proteins and their dynamics, however, still challenges conventional techniques. Here we report the first attempt to immobilize membrane protein complexes on surface-enhanced Raman scattering (SERS)-active supports, titanium dioxide-coated silver (Ag@TiO2) nanoparticles. Biocompatible immobilization of microsomal monooxygenase complexes is achieved through lipid fission and fusion. SERS activity of the Ag@TiO2 nanoparticles enables in situ monitoring of protein-protein electron transfer and enzyme catalysis in real time. Through SERS fingerprints of the monooxygenase redox centers, the correlations between these protein-ligand interactions and reactive oxygen species generation are revealed, providing novel insights into the molecular mechanisms underlying monooxygenase-mediated apoptotic regulation. This study offers a novel strategy to explore structure-function relationships of membrane protein complexes and has the potential to advance the development of novel reactive oxygen species-inducing drugs for cancer therapy.

Transferable Optical Enhancement Nanostructures by Gapless Stencil Lithography.

Optical spectroscopy techniques are central for the characterization of two-dimensional (2D) quantum materials. However, the reduced volume of atomically thin samples often results in a cross section that is far too low for conventional optical methods to produce measurable signals. In this work, we developed a scheme based on the stencil lithography technique to fabricate transferable optical enhancement nanostructures for Raman and photoluminescence spectroscopy. Equipped with this new nanofabrication technique, we designed and fabricated plasmonic nanostructures to tailor the interaction of few-layer materials with light. We demonstrate orders-of-magnitude increase in the Raman intensity of ultrathin flakes of 2D semiconductors and magnets as well as selective Purcell enhancement of quenched excitons in WSe2/MoS2 heterostructures. We provide evidence that the method is particularly effective for air-sensitive materials, as the transfer can be performed in situ. The fabrication technique can be generalized to enable a high degree of flexibility for functional photonic devices.

From Bulk to Single Molecules: Surface-Enhanced Raman Scattering of Cytochrome C Using Plasmonic DNA Origami Nanoantennas.

Cytochrome C, an evolutionarily conserved protein, plays pivotal roles in cellular respiration and apoptosis. Understanding its molecular intricacies is essential for both academic inquiry and potential biomedical applications. This study introduces an advanced single-molecule surface-enhanced Raman scattering (SM-SERS) system based on DNA origami nanoantennas (DONAs), optimized to provide unparalleled insights into protein structure and interactions. Our system effectively detects shifts in the Amide III band, thereby elucidating protein dynamics and conformational changes. Additionally, the system permits concurrent observations of oxidation processes and Amide bands, offering an integrated view of protein structural and chemical modifications. Notably, our approach diverges from traditional SM-SERS techniques by de-emphasizing resonance conditions for SERS excitation, aiming to mitigate challenges like peak oversaturation. Our findings underscore the capability of our DONAs to illuminate single-molecule behaviors, even within aggregate systems, providing clarity on molecular interactions and behaviors.

Jellyfish-like Gold Nanowires as FlexoSERS Sensors for Sweat Analysis.

We introduce the FlexoSERS sensor, which is notable for its high stretchability, sensitivity, and patternability. Featuring a hierarchically oriented jellyfish-like architecture constructed from stretchable gold nanowires, this sensor provides an ultrasensitive SERS signal even under 50% strain, with an enhancement factor (EF) of 3.3 × 1010. Impressively, this heightened performance remains consistently robust across 2,500 stretch-release cycles. The integration of nanowires with 3D-printed hydrogel enables a customizable FlexoSERS sensor, facilitating localized sweat collection and detection. The FlexoSERS sensor successfully detects and quantifies uric acid (UA) in both artificial and human sweat and functions as a pH sensor with repeatability and sensitivity across a pH range of 4.2-7.8, enabling real-time sweat monitoring during exercise. In summary, the rational architectural design, scalable fabrication process, and hydrogel integration collectively position this nanowire-based FlexoSERS sensor as a highly promising platform for customizable wearable sweat diagnostics.

Customized Self-Assembled Gold Nanoparticle-DNA Origami Composite Templates for Shape-Directed Growth of Plasmonic Structures.

The metal plasmonic nanostructure has the optical property of plasmon resonance, which holds great potential for development in nanophotonics, bioelectronics, and molecular detection. However, developing a general and straightforward method to prepare metal plasmonic nanostructures with a controllable size and morphology still poses a challenge. Herein, we proposed a synthesis strategy that utilized a customizable self-assembly template for shape-directed growth of metal structures. We employed gold nanoparticles (AuNPs) as connectors and DNA nanotubes as branches, customizing gold nanoparticle-DNA origami composite nanostructures with different branches by adjusting the assembly ratio between the connectors and branches. Subsequently, various morphologies of plasmonic metal nanostructures were created using this template shape guided strategy, which exhibited enhancement of surface-enhanced Raman scattering (SERS) signals. This strategy provides a new approach for synthesizing metallic nanostructures with multiple morphologies and opens up another possibility for the development of customizable metallic plasmonic structures with broader applications.

Metal-Organic Framework-Based Surface-Enhanced Raman Scattering Sensing Platform for Trace Malondialdehyde Detection in Tears.

Disease biomarkers in tears are crucial for clinical diagnosis and health monitoring. However, the limited volume of tear samples, low concentration of tear biomarkers, and complex tear composition present challenges for precise testing. We introduce a spot-on testing platform of metal-organic framework (MOF)-based surface-enhanced Raman scattering (SERS) capillary column, which is capable of target molecules selective separation and enrichment for tear biomarkers in situ detection. It consists of Au nanostars for effective SERS signal and a porous MOF shell for separating impurities through molecular sieving effect. This platform allows for simultaneous collection and detection of tear, capturing the disease biomarker malondialdehyde in tears with a 9.38 × 10-9 mol/L limit of detection. Moreover, we designed a hand-held device based on this tubular SERS sensor, successfully diagnosing patients with dry eye disease. This functional capillary column enables noninvasive and rapid diagnosis of biomarkers in biofluids, providing potential for disease diagnosis and healthcare monitoring.

Adaptive Gap-Tunable Surface-Enhanced Raman Spectroscopy.

Gap plasmon (GP) resonance in static surface-enhanced Raman spectroscopy (SERS) structures is generally too narrow and not tunable. Here, we present an adaptive gap-tunable SERS device to selectively enhance and modulate different vibrational modes via active flexible Au nanogaps, with adaptive optical control. The tunability of GP resonance is up to ∼1200 cm-1 by engineering gap width, facilitated by mechanical bending of a polyethylene terephthalate substrate. We confirm that the tuned GP resonance selectively enhances different Raman spectral regions of the molecules. Additionally, we dynamically control the SERS intensity through the wavefront shaping of excitation beams. Furthermore, we demonstrate simulation results, exhibiting the mechanical and optical properties of a one-dimensional flexible nanogap and their advantage in high-speed biomedical sensing. Our work provides a unique approach for observing and controlling the enhanced chemical responses with dynamic tunability.

Three-Dimensional Au Octahedral Nanoheptamers: Single-Particle and Bulk Near-Field Focusing for Surface-Enhanced Raman Scattering.

Herein, we present a synthetic approach to fabricate Au nanoheptamers composed of six individual Au nanospheres interconnected through thin metal bridges arranged in an octahedral configuration. The resulting structures envelop central Au nanospheres, producing Au nanosphere heptamers with an open architectural arrangement. Importantly, the initial Pt coating of the Au nanospheres is a crucial step for protecting the inner Au nanospheres during multiple reactions. As-synthesized Au nanoheptamers exhibit multiple hot spots formed by nanogaps between nanospheres, resulting in strong electromagnetic near-fields. Additionally, we conducted surface-enhanced Raman-scattering-based detection of a chemical warfare agent simulant in the gas phase and achieved a limit of detection of 100 ppb, which is 3 orders lower than that achieved using Au nanospheres and Au nanohexamers. This pseudocore-shell nanostructure represents a significant advancement in the realm of complex nanoparticle synthesis, moving the field one step closer to sophisticated nanoparticle engineering.

Plasmonic Annular Nanotrenches with 1 nm Nanogaps for Detection of SARS-CoV-2 Using SERS-Based Immunoassay.

This study represents the synthesis of a novel class of nanoparticles denoted as annular Au nanotrenches (AANTs). AANTs are engineered to possess embedded, narrow circular nanogaps with dimensions of approximately 1 nm, facilitating near-field focusing for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via a surface-enhanced Raman scattering (SERS)-based immunoassay. Notably, AANTs exhibited an exceedingly low limit of detection (LOD) of 1 fg/mL for SARS-CoV-2 spike glycoproteins, surpassing the commercially available enzyme-linked immunosorbent assay (ELISA) by 6 orders of magnitude (1 ng/mL from ELISA). To assess the real-world applicability, a study was conducted on 50 clinical samples using an SERS-based immunoassay with AANTs. The results revealed a sensitivity of 96% and a selectivity of 100%, demonstrating the significantly enhanced sensing capabilities of the proposed approach in comparison to ELISA and commercial lateral flow assay kits.

Two-Orders-of-Magnitude Enhancement of SERS Activity via a Simple Surface Engineering of Quasi-Metal Single-Crystal Frameworks.

Beyond noble metals and semiconductors, quasi-metals have recently been shown to be noteworthy substrates for surface enhanced Raman spectroscopy, and their excellent quasi-metal surface-enhanced Raman spectroscopy (SERS) sensing has demonstrated a wider range of application scenarios. However, the underlying mechanism behind the enhanced Raman activity is still unclear. Here, we demonstrate that surface hydroxyls play a crucial role in the enhancement of the SERS activity of quasi-metal nanostructures. As a demonstration material, quasi-metallic MoO2 single-crystal frameworks rich in surface hydroxyls have been shown to have 100 times higher SERS activity than MoO2 single-crystal frameworks without hydroxyl functionalization, with a Raman enhancement factor of up to 7.6 × 107. Experimental and first-principles density-functional theory calculation results show that the enhanced Raman activity can be attributed to an effective interfacial charge transfer within the MoO2/OH/molecule system.

Patterned Gold Nanoparticle Superlattice Film for Wearable Sweat Sensors.

Nanoparticle superlattices are beneficial in terms of providing strong and uniform signals in analysis owing to their closely packed uniform structures. However, nanoparticle superlattices are prone to cracking during physical activities because of stress concentrations, which hinders their detection performance and limits their analytical applications. In this work, template printing methods were used in this study to prepare a patterned gold nanoparticle (AuNP) superlattice film. By adjustment of the size of the AuNP superlattice domain below the critical size of fracture, the mechanical stability of the AuNP superlattice domain is improved. Thus, long-term sustainable high-performance signal output is achieved. The patterned AuNP superlattice film was used to construct a wearable sweat sensor based on surface-enhanced Raman scattering (SERS). The designed sensor showed promise for long-term reliable use in actual scenarios in terms of recommending water replenishment, monitoring hydration states, and tracking the intensity of activity.

Yolk-Shell Hierarchical Pore Au@MOF Nanostructures: Efficient Gas Capture and Enrichment for Advanced Breath Analysis.

Surface-enhanced Raman scattering (SERS) offers a promising, cost-effective alternative for the rapid, sensitive, and quantitative analysis of potential biomarkers in exhaled gases, which is crucial for early disease diagnosis. However, a major challenge in SERS is the effective detection of gaseous analytes, primarily due to difficulties in enriching and capturing them within the substrate's "hotspot" regions. This study introduces an advanced gas sensor combining mesoporous gold (MesoAu) and metal-organic frameworks (MOFs), exhibiting high sensitivity and rapid detection capabilities. The MesoAu provides abundant active sites and interconnected mesopores, facilitating the diffusion of analytes for detection. A ZIF-8 shell enveloping MesoAu further enriches target molecules, significantly enhancing sensitivity. A proof-of-concept experiment demonstrated a detection limit of 0.32 ppb for gaseous benzaldehyde, indicating promising prospects for the rapid diagnosis of early stage lung cancer. This research also pioneers a novel approach for constructing hierarchical plasmonic nanostructures with immense potential in gas sensing.

Rapid discrimination of four Salmonella enterica serovars: A performance comparison between benchtop and handheld Raman spectrometers.

Foodborne illnesses, particularly those caused by Salmonella enterica with its extensive array of over 2600 serovars, present a significant public health challenge. Therefore, prompt and precise identification of S. enterica serovars is essential for clinical relevance, which facilitates the understanding of S. enterica transmission routes and the determination of outbreak sources. Classical serotyping methods via molecular subtyping and genomic markers currently suffer from various limitations, such as labour intensiveness, time consumption, etc. Therefore, there is a pressing need to develop new diagnostic techniques. Surface-enhanced Raman spectroscopy (SERS) is a non-invasive diagnostic technique that can generate Raman spectra, based on which rapid and accurate discrimination of bacterial pathogens could be achieved. To generate SERS spectra, a Raman spectrometer is needed to detect and collect signals, which are divided into two types: the expensive benchtop spectrometer and the inexpensive handheld spectrometer. In this study, we compared the performance of two Raman spectrometers to discriminate four closely associated S. enterica serovars, that is, S. enterica subsp. enterica serovar dublin, enteritidis, typhi and typhimurium. Six machine learning algorithms were applied to analyse these SERS spectra. The support vector machine (SVM) model showed the highest accuracy for both handheld (99.97%) and benchtop (99.38%) Raman spectrometers. This study demonstrated that handheld Raman spectrometers achieved similar prediction accuracy as benchtop spectrometers when combined with machine learning models, providing an effective solution for rapid, accurate and cost-effective identification of closely associated S. enterica serovars.

DNA Origami-Engineered Plasmonic Nanoprobes for Targeted Cancer Imaging.

Plasmonic nanomaterials bearing targeting ligands are of great interest for surface-enhanced Raman scattering (SERS)-based bioimaging applications. However, the practical utility of SERS-based imaging strategies has been hindered by the lack of a straightforward method to synthesize highly sensitive SERS-active nanostructures with high yield and efficiency. In this work, leveraging DNA origami principles, we report the first-in-class design of a SERS-based plasmonically coupled nanoprobe for targeted cancer imaging (SPECTRA). The nanoprobe harnesses a cancer cell targeting DNA aptamer sequence and vibrational tag with stretching frequency in the cell-silent Raman window. Through the integration of aptamer sequence specific for DU145 cells, we show the unique capabilities of SPECTRA for targeted imaging of DU145 cells. Our results demonstrate that the scalability, cost-effectiveness, and reproducibility of this method of fabrication of SERS nanoprobes can serve as a versatile platform for creating nanoprobes with broad applications in the fields of cancer biology and biomedical imaging.

2D Film-Like Magnetic SERS Tag with Enhanced Capture and Detection Abilities for Immunochromatographic Diagnosis of Multiple Bacteria.

Here, a multiplex surface-enhanced Raman scattering (SERS)-immunochromatography (ICA) platform is presented using a graphene oxide (GO)-based film-like magnetic tag (GFe-DAu-D/M) that effectively captures and detects multiple bacteria in complex specimens. The 2D GFe-DAu-D/M tag with universal bacterial capture ability is fabricated through the layer-by-layer assembly of one layer of small Fe3O4 nanoparticles (NPs) and two layers of 30 nm AuNPs with a 0.5 nm built-in nanogap on monolayer GO nanosheets followed by co-modification with 4-mercaptophenylboronic acid (MPBA) and 5,5'-dithiobis-(2-nitrobenzoic acid).The GFe-DAu-D/M enabled the rapid enrichment of multiple bacteria by MPBA and quantitative analysis of target bacteria on test lines by specific antibodies, thus achieving multiple signal amplification of magnetic enrichment effect and multilayer dense hotspots and eliminating matrix interference in real-world applications. The developed technology can directly and simultaneously diagnose three major pathogens (Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella typhimurium) with detection limits down to the level of 10 cells mL-1. The good performance of the proposed method in the detection of real urinary tract infection specimens is also demonstrated, suggesting the great potential of the GFe-DAu-D/M-ICA platform for the highly sensitive monitoring of bacterial infections or contamination.

Biomimetic Gold Nanorods-Manganese Porphyrins with Surface-Enhanced Raman Scattering Effect for Photoacoustic Imaging-Guided Photothermal/Photodynamic Therapy.

Surface-enhanced Raman scattering (SERS) imaging integrating photothermal and photodynamic therapy (PTT/PDT) is a promising approach for achieving accurate diagnosis and effective treatment of cancers. However, most available Raman reporters show multiple signals in the fingerprint region, which overlap with background signals from cellular biomolecules. Herein, a 4T1 cell membrane-enveloped gold nanorods-manganese porphyrins system (GMCMs) is designed and successfully fabricated as a biomimetic theranostic nanoplatform. Manganese porphyrins are adsorbed on the surface of Au nanorods via the terminal alkynyl group. Cell membrane encapsulation protects the manganese porphyrins from falling off the gold nanorods. The biomimetic GMCMs confirm specific homologous targeting to 4T1 cells with good dispersibility, excellent photoacoustic (PA) imaging properties, and preferable photothermal and 1O2 generation performance. GMCMs exhibit distinct SERS signals in the silent region without endogenous biomolecule interference both in vitro and in vivo. Manganese ions could not only quench the fluorescence of porphyrins to enhance the SERS imaging effect but also deplete cellular GSH to increase 1O2 yield. Both in vitro and in vivo studies demonstrate that GMCMs effectively eradicate tumors through SERS/PA imaging-guided PTT/PDT. This study provides a feasible strategy for augmenting the Raman imaging effects of the alkynyl group and integrating GSH-depletion to enhance PTT/PDT efficacy.