This review summarizes recent SERS developments, focusing on analyte manipulation strategies and hybrid SERS platforms that venture beyond hotspot engineering.

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.

Successful translation of laboratory-based surface-enhanced Raman scattering (SERS) platforms to clinical applications requires multiplex and ultratrace detection of small metabolites from a complex biofluid. However, these metabolites 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, a 'confine-and-capture' approach is demonstrated for multiplex detection of two families of urine metabolites correlated with miscarriage risks, 5β-pregnane-3α,20α-diol-3α-glucuronide and tetrahydrocortisone. To enhance SERS signals by 10 12 -fold, specific nanoscale surface chemistry is used for targeted metabolite capture from a complex urine matrix prior to confining them on a superhydrophobic SERS platform. Applying chemometrics, including principal component analysis and partial least square regression, enables conversion of molecular fingerprint information into quantifiable readouts. The whole screening procedure requires only 30 minutes, including urine pretreatment, sample drying on the SPHB-mirror 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.Keywords. surface-enhanced Raman spectroscopy (SERS), superhydrophobic SERS platform, chemometrics, metabolomics, urine-based diagnostic test 3 Achieving ultratrace detection of small molecules with low Raman scattering cross-sections and without specific affinity to plasmonic nanoparticle surfaces remains challenging in surfaceenhanced Raman scattering (SERS) spectroscopy. [1][2][3] This difficulty is further compounded by the need to perform multiplex and quantitative molecular detection from a complex matrix.Successfully addressing these issues is instrumental towards the translating laboratory-based SERS platforms into practical sensing devices. 4 SERS offers multiple advantages over conventional analytical platforms such as fluorescence-based techniques. 5 SERS platforms can be tailored to generate intense electromagnetic field enhancements and dense plasmonic hotspots, in turn enhancing molecule-specific Raman vibrational fingerprint intensities by >10 9 -fold. 6,7 These fingerprints exhibit substantially narrower peak widths as compared to the broad fluorescence emission bands (full-width half-maximum of ~ 2 nm versus 30 nm respectively), further enabling SERS to achieve label-free multiplex analysis with ease. 8 SERS measurements also require significantly shorter time as compared to conventional chromatography-or mass spectrometrybased analytical approaches, whereby SERS analyses can be completed within an hour. 9 More importantly, the fingerprint specificity of SERS readouts enables differentiation of isomeric structures which cannot be easily achieved using other techniques. [10][11][12] However, majority of current SERS research focus predominantly on platform design, using s...

Stand-off Raman spectroscopy combines the superior 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 molecular trapping metal-organic framework (MOF)-integrated SERS platform. Formed via the self-assembly of Ag@MOF core-shell nanoparticles, our 3D plasmonic architecture exhibits micrometer-sized thick hotspot to allow active sorption and rapid detection of aerosols, gas and volatile organic compounds down to parts-per-billion level, notably up to 10 meters. The platform is also 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 hydrocarbons (PAH) mixtures in real-time under outdoor daylight. By overcoming core challenges in current remote Raman spectroscopy, our strategy creates enormous opportunity in the long-distance and sensitive monitoring of air/gaseous environment at the molecular level, especially important in environmental conservation, disaster prevention and homeland defense.

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.