Emerging nanosensor platforms and machine learning strategies toward rapid, point-of-need small-molecule metabolite detection and monitoring.

Speedy, point-of-need detection and monitoring of small-molecule metabolites are vital across diverse applications ranging from biomedicine to agri-food and environmental surveillance. Nanomaterial-based sensor (nanosensor) platforms are rapidly emerging as excellent candidates for versatile and ultrasensitive detection owing to their highly configurable optical, electrical and electrochemical properties, fast readout, as well as portability and ease of use. To translate nanosensor technologies for real-world applications, key challenges to overcome include ultralow analyte concentration down to ppb or nM levels, complex sample matrices with numerous interfering species, difficulty in differentiating isomers and structural analogues, as well as complex, multidimensional datasets of high sample variability. In this Perspective, we focus on contemporary and emerging strategies to address the aforementioned challenges and enhance nanosensor detection performance in terms of sensitivity, selectivity and multiplexing capability. We outline 3 main concepts: (1) customization of designer nanosensor platform configurations via chemical- and physical-based modification strategies, (2) development of hybrid techniques including multimodal and hyphenated techniques, and (3) synergistic use of machine learning such as clustering, classification and regression algorithms for data exploration and predictions. These concepts can be further integrated as multifaceted strategies to further boost nanosensor performances. Finally, we present a critical outlook that explores future opportunities toward the design of next-generation nanosensor platforms for rapid, point-of-need detection of various small-molecule metabolites.

Inducing Ring Complexation for Efficient Capture and Detection of Small Gaseous Molecules Using SERS for Environmental Surveillance.

Gas-phase surface-enhanced Raman scattering (SERS) remains challenging due to poor analyte affinity to SERS substrates. The reported use of capturing probes suffers from concurrent inconsistent signals and long response time due to the formation of multiple potential probe-analyte interaction orientations. Here, we demonstrate the use of multiple non-covalent interactions for ring complexation to boost the affinity of small gas molecules, SO2 and NO2 , to our SERS platform, achieving rapid capture and multiplex detection down to 100 ppm. Experimental and in-silico studies affirm stable ring complex formation, and kinetic investigations reveal a 4-fold faster response time compared to probes without stable ring complexation capability. By synergizing spectral concatenation and support vector machine regression, we achieve 91.7 % accuracy for multiplex quantification of SO2 and NO2 in excess CO2 , mimicking real-life exhausts. Our platform shows immense potential for on-site exhaust and air quality surveillance.

Noninvasive and Point-of-Care Surface-Enhanced Raman Scattering (SERS)-Based Breathalyzer for Mass Screening of Coronavirus Disease 2019 (COVID-19) under 5 min.

Population-wide surveillance of COVID-19 requires tests to be quick and accurate to minimize community transmissions. The detection of breath volatile organic compounds presents a promising option for COVID-19 surveillance but is currently limited by bulky instrumentation and inflexible analysis protocol. Here, we design a hand-held surface-enhanced Raman scattering-based breathalyzer to identify COVID-19 infected individuals in under 5 min, achieving >95% sensitivity and specificity across 501 participants regardless of their displayed symptoms. Our SERS-based breathalyzer harnesses key variations in vibrational fingerprints arising from interactions between breath metabolites and multiple molecular receptors to establish a robust partial least-squares discriminant analysis model for high throughput classifications. Crucially, spectral regions influencing classification show strong corroboration with reported potential COVID-19 breath biomarkers, both through experiment and in silico. Our strategy strives to spur the development of next-generation, noninvasive human breath diagnostic toolkits tailored for mass screening purposes.

Enantiospecific Molecular Fingerprinting Using Potential-Modulated Surface-Enhanced Raman Scattering to Achieve Label-Free Chiral Differentiation.

Chiral differentiation is critical in diverse fields ranging from pharmaceutics to chiral synthesis. While surface-enhanced Raman scattering (SERS) offers molecule-specific vibrational information with high detection sensitivity, current strategies rely on indirect detection using additional selectors and cannot exploit SERS' key advantages for univocal and generic chiral differentiation. Here, we achieve direct, label-free SERS sensing of biologically important enantiomers by synergizing asymmetric nanoporous gold (NPG) nanoparticles with electrochemical-SERS to generate enantiospecific molecular fingerprints. Experimental and in silico studies reveal that chiral recognition is two pronged. First, the numerous surface atomic defects in NPG provide the necessary localized asymmetric environment to induce enantiospecific molecular adsorptions and interaction affinities. Concurrently, the applied potential drives and orients the enantiomers close to the NPG surface for maximal analyte-surface interactions. Notably, our strategy is versatile and can be readily extended to detect various enantiomers. Furthermore, we can achieve multiplex quantification of enantiomeric ratios with excellent predictive performance. Our combinatorial approach thus offers an important paradigm shift from current approaches to achieve label-free chiral SERS sensing of various enantiomers.

ZIF-Induced d-Band Modification in a Bimetallic Nanocatalyst: Achieving Over 44 % Efficiency in the Ambient Nitrogen Reduction Reaction.

The electrochemical nitrogen reduction reaction (NRR) offers a sustainable solution towards ammonia production but suffers poor reaction performance owing to preferential catalyst-H formation and the consequential hydrogen evolution reaction (HER). Now, the Pt/Au electrocatalyst d-band structure is electronically modified using zeolitic imidazole framework (ZIF) to achieve a Faradaic efficiency (FE) of >44 % with high ammonia yield rate of >161 µg mgcat -1 h-1 under ambient conditions. The strategy lowers electrocatalyst d-band position to weaken H adsorption and concurrently creates electron-deficient sites to kinetically drive NRR by promoting catalyst-N2 interaction. The ZIF coating on the electrocatalyst doubles as a hydrophobic layer to suppress HER, further improving FE by >44-fold compared to without ZIF (ca. 1 %). The Pt/Au-NZIF interaction is key to enable strong N2 adsorption over H atom.

Multiplex Surface-Enhanced Raman Scattering Identification and Quantification of Urine Metabolites in Patient Samples within 30 min.

Successful translation of laboratory-based surface-enhanced Raman scattering (SERS) platforms to clinical applications requires multiplex and ultratrace detection of small biomarker molecules from a complex biofluid. However, these biomarker molecules generally exhibit low Raman scattering cross sections and do not possess specific affinity to plasmonic nanoparticle surfaces, significantly increasing the challenge of detecting them at low concentrations. Herein, we demonstrate a "confine-and-capture" approach for multiplex detection of two families of urine metabolites correlated with miscarriage risks, 5ß-pregnane-3α,20α-diol-3α-glucuronide and tetrahydrocortisone. To enhance SERS signals by 1012-fold, we use specific nanoscale surface chemistry for targeted metabolite capture from a complex urine matrix prior to confining them on a superhydrophobic SERS platform. We then apply chemometrics, including principal component analysis and partial least-squares regression, to convert molecular fingerprint information into quantifiable readouts. The whole screening procedure requires only 30 min, including urine pretreatment, sample drying on the SERS platform, SERS measurements, and chemometric analyses. These readouts correlate well with the pregnancy outcomes in a case-control study of 40 patients presenting threatened miscarriage symptoms.

Two-Photon-Assisted Polymerization and Reduction: Emerging Formulations and Applications.

Two-photon lithography (TPL) is an emerging approach to fabricate complex multifunctional micro/nanostructures. This is because TPL can easily develop various 2D and 3D structures on a variety of surfaces, and there has been a rapidly expanding pool of processable photoresists to create different materials. However, challenges in developing two-photon processable photoresists currently impede progress in TPL. In this review, we critically discuss the importance of photoresist formulation in TPL. We begin by evaluating the commercial photoresists to design micro/nanostructures for promising applications in anti-counterfeiting, superomniphobicity, and micromachines with movable parts. Next, we discuss emerging hydrogel/organogel photoresists, focusing on customizing photoresist formulations to fabricate reconfigurable structures that can respond to changes in local pH, solvent, and temperature. We also review the development of metal salt-based photoresists for direct metal writing, whereby various formulations have been developed to enable applications in online sensing, catalysis, and electronics. Finally, we provide a critical outlook and highlight various outstanding challenges in formulating processable photoresists for TPL.

Tracking Airborne Molecules from Afar: Three-Dimensional Metal-Organic Framework-Surface-Enhanced Raman Scattering Platform for Stand-Off and Real-Time Atmospheric Monitoring.

Stand-off Raman spectroscopy combines the advantages of both Raman spectroscopy and remote detection to retrieve molecular vibrational fingerprints of chemicals at inaccessible sites. However, it is currently restricted to the detection of pure solids and liquids and not widely applicable for dispersed molecules in air. Herein, we realize real-time stand-off SERS spectroscopy for remote and multiplex detection of atmospheric airborne species by integrating a long-range optic system with a 3D analyte-sorbing metal-organic framework (MOF)-integrated SERS platform. Formed via the self-assembly of Ag@MOF core-shell nanoparticles, our 3D plasmonic architecture exhibits micrometer thick SERS hotspot to allow active sorption and rapid detection of aerosols, gas, and volatile organic compounds down to parts-per-billion levels, notably at a distance up to 10 m apart. The platform is highly sensitive to changes in atmospheric content, as demonstrated in the temporal monitoring of gaseous CO2 in several cycles. Importantly, we demonstrate the remote and multiplex quantification of polycyclic aromatic hydrocarbon mixtures in real time under outdoor daylight. By overcoming core challenges in current remote Raman spectroscopy, our strategy creates an opportunity in the long-distance and sensitive monitoring of air/gaseous environment at the molecular level, which is especially important in environmental conservation, disaster prevention, and homeland defense.

Three-Dimensional Surface-Enhanced Raman Scattering Platforms: Large-Scale Plasmonic Hotspots for New Applications in Sensing, Microreaction, and Data Storage.

Surface-enhanced Raman scattering (SERS) is a molecular-specific spectroscopic technique that provides up to 1010-fold enhancement of signature Raman fingerprints using nanometer-scale 0D to 2D platforms. Over the past decades, 3D SERS platforms with additional plasmonic materials in the z-axis have been fabricated at sub-micrometer to centimeter scale, achieving higher hotspot density in all x, y, and z spatial directions and higher tolerance to laser misalignment. Moreover, the flexibility to construct platforms in arbitrary sizes and 3D shapes creates attractive applications besides traditional SERS sensing. In this Account, we introduce our library of substrate-based and substrate-less 3D plasmonic platforms, with an emphasis on their non-sensing applications as microlaboratories and data storage labels. We aim to provide a scientific synopsis on these high-potential yet currently overlooked applications of SERS and ignite new scientific discoveries and technology development in 3D SERS platforms to tackle real-world issues. One highlight of our substrate-based SERS platforms is multilayered platforms built from micrometer-thick assemblies of plasmonic particles, which can achieve up to 1011 enhancement factor. As an alternative, constructing 3D hotspots on non-plasmonic supports significantly reduces waste of plasmonic materials while allowing high flexibility in structural design. We then introduce our emerging substrate-less plasmonic capsules including liquid marbles and colloidosomes, which we further incorporate the latter within an aerosol to form centimeter-scale SERS-active plasmonic cloud, the world's largest 3D SERS platform to date. We then discuss the various emerging applications arising only from these 3D platforms, in the fields of sensing, microreactions, and data storage. An important novel sensing application is the stand-off detection of airborne analytes that are several meters away, made feasible with aerosolized plasmonic clouds. We also describe plasmonic capsules as excellent miniature lab-in-droplets that can simultaneously provide in situ monitoring at the molecular level during reaction, owing to their ultrasensitive 3D plasmonic shells. We highlight the emergence of 3D SERS-based data storage platforms with 10-100-fold higher storage density than 2D platforms, featuring a new approach in the development of level 3 security (L3S) anti-counterfeiting labels. Ultimately, we recognize that 3D SERS research can only be developed further when its sensing capabilities are concurrently strengthened. With this vision, we foresee the creation of highly applicable 3D SERS platforms that excel in both sensing and non-sensing areas, providing modern solutions in the ongoing Fourth Industrial Revolution.

Plasmonic-induced overgrowth of amorphous molybdenum sulfide on nanoporous gold: An ambient synthesis method of hybrid nanoparticles with enhanced electrocatalytic activity.

Hybrid materials of earth abundant transition metal dichalcogenides and noble metal nanoparticles, such as molybdenum sulfide (MoSx) and gold nanoparticles, exhibit synergistic effects that can enhance electrocatalytic reactions. However, most current hybrid MoSx-gold synthesis requires an energy intensive heat source of >500 °C or chemical plating to achieve deposition of MoSx on the gold surface. Herein, we demonstrate the direct overgrowth of MoSx over colloidal nanoporous gold (NPG), conducted feasibly under ambient conditions, to form hybrid particles with enhanced electrocatalytic performance toward hydrogen evolution reaction. Our strategy exploits the localized surface plasmon resonance-mediated photothermal heating of NPG to achieve >230 °C surface temperature, which induces the decomposition of the (NH4)2MoS4 precursor and direct overgrowth of MoSx over NPG. By tuning the concentration ratio between the precursor and NPG, the amount of MoSx particles deposited can be systematically controlled from 0.5% to 2% of the Mo/(Au + Mo) ratio. Importantly, we find that the hybrid particles exhibit higher bridging and an apical S to terminal S atomic ratio than pure molybdenum sulfide, which gives rise to their enhanced electrocatalytic performance for hydrogen evolution reaction. We demonstrate that hybrid MoSx-NPG exhibits >30 mV lower onset potential and a 1.7-fold lower Tafel slope as compared to pure MoSx. Our methodology provides an energy- and cost-efficient synthesis pathway, which can be extended to the synthesis of various functional hybrid structures with unique properties for catalysis and sensing applications.

Designing surface-enhanced Raman scattering (SERS) platforms beyond hotspot engineering: emerging opportunities in analyte manipulations and hybrid materials.

Surface-enhanced Raman scattering (SERS) is a molecule-specific spectroscopic technique with diverse applications in (bio)chemistry, clinical diagnosis and toxin sensing. While hotspot engineering has expedited SERS development, it is still challenging to detect molecules with no specific affinity to plasmonic surfaces. With the aim of improving detection performances, we venture beyond hotspot engineering in this tutorial review and focus on emerging material design strategies to capture and confine analytes near SERS-active surfaces as well as various promising hybrid SERS platforms. We outline five major approaches to enhance SERS performance: (1) enlarging Raman scattering cross-sections of non-resonant molecules via chemical coupling reactions; (2) targeted chemical capturing of analytes through surface-grafted agents to localize them on plasmonic surfaces; (3) physically confining liquid analytes on non-wetting SERS-active surfaces and (4) confining gaseous analytes using porous materials over SERS hotspots; (5) synergizing conventional metal-based SERS platforms with functional materials such as graphene, semiconducting materials, and piezoelectric polymers. These approaches can be integrated with engineered hotspots as a multifaceted strategy to further boost SERS sensitivities that are unachievable using hotspot engineering alone. Finally, we highlight current challenges in this research area and suggest new research directions towards efficient SERS designs critical for real-world applications.

Concentrating Immiscible Molecules at Solid@MOF Interfacial Nanocavities to Drive an Inert Gas-Liquid Reaction at Ambient Conditions.

Gas-liquid reactions form the basis of our everyday lives, yet they still suffer poor reaction efficiency and are difficult to monitor in situ, especially at ambient conditions. Now, an inert gas-liquid reaction between aniline and CO2 is driven at 1 atm and 298 K by selectively concentrating these immiscible reactants at the interface between metal-organic framework and solid nanoparticles (solid@MOF). Real-time reaction SERS monitoring and simulations affirm the formation of phenylcarbamic acid, which was previously undetectable because they are unstable for post-reaction treatments. The solid@MOF ensemble gives rise to a more than 28-fold improvement to reaction efficiency as compared to ZIF-only and solid-only platforms, emphasizing that the interfacial nanocavities in solid@MOF are the key to enhance the gas-liquid reaction. Our strategy can be integrated with other functional materials, thus opening up new opportunities for ambient-operated gas-liquid applications.

Plasmonic nose: integrating the MOF-enabled molecular preconcentration effect with a plasmonic array for recognition of molecular-level volatile organic compounds.

Timely detection of toxic vapor is vital for safeguarding people's lives. Herein, we design a plasmonic nose based on a zeolitic imidazolate framework (ZIF)-encapsulated Ag nanocube array for ultratrace recognition of VOC vapor. The plasmonic nose enables in situ adsorption kinetics and recognition of various VOCs at ppm levels, eliminating false positives. Our approach provides a paradigm shift to next-generation, effective and specific gas sensors.

A Chemical Approach To Break the Planar Configuration of Ag Nanocubes into Tunable Two-Dimensional Metasurfaces.

Current plasmonic metasurfaces of nanocubes are limited to planar configurations, restricting the ability to create tailored local electromagnetic fields. Here, we report a new chemical strategy to achieve tunable metasurfaces with nonplanar nanocube orientations, creating novel lattice-dependent field localization patterns. We manipulate the interfacial behaviors of Ag nanocubes by controlling the ratio of hydrophilic/hydrophobic molecules added in a binary thiol mixture during the surface functionalization step. The nanocube orientation at an oil/water interface can consequently be continuously tuned from planar to tilted and standing configurations, leading to the organization of Ag nanocubes into three unique large-area metacrystals, including square close-packed, linear, and hexagonal lattices. In particular, the linear and hexagonal metacrystals are unusual open lattices comprising nonplanar nanocubes, creating unique local electromagnetic field distribution patterns. Large-area "hot hexagons" with significant delocalization of hot spots form in the hexagonal metacrystal. With a lowest packing density of 24%, the hexagonal metacrystal generates nearly 350-fold stronger surface-enhanced Raman scattering as compared to the other denser-packing metacrystals, demonstrating the importance of achieving control over the geometrical and spatial orientation of the nanocubes in the metacrystals.