Surface-enhanced Raman scattering (SERS) is an ultrasensitive analytical technique, which is capable of providing high specificity, thus it can be used for toxicological drug assay (detection and quantification). However, SERS-based drug analysis directly in human biofluids requires mitigation of fouling and non-specificity effects that are commonly appeared from unwanted adsorption of endogenous biomolecules present in biofluids (e.g., blood plasma and serum) onto the SERS substrate. Here we report a bottom-up fabrication strategy to prepare ultrasensitive SERS substrates, firstly by functionalizing chemically synthesized gold triangular nanoprisms (Au TNPs) with poly(ethylene glycol)-thiolate in solid-state to avoid protein fouling, and secondly by generating flexible plasmonic patches to enhance SERS sensitivity via the formation of high intensity electromagnetic hot spots. Poly(ethylene glycol)-thiolate-functionalized Au TNPs in the form of flexible plasmonic patches show two-fold improved signal-to-noise ratio in comparison to triethylamine-passivated Au TNPs. Furthermore, the plasmonic patches display a SERS enhancement factor of 4.5 x 10 7 . Utilizing the Langmuir adsorption model we determine the adsorption constant of drugs for two different surface ligands and observed that the drug molecules display stronger affinity for poly(ethylene glycol) ligands than triethylamine. Our density functional theory calculations unequivocally support the interaction between drug molecules and poly(ethylene glycol) moieties. Furthermore, the universality of the plasmonic patch for SERSbased drug detection is demonstrated for cocaine, JWH-018, and opioids (fentanyl, despropionyl fentanyl, and heroin) and binary mixture (trace amount of fentanyl in heroin) analysis. We demonstrate that applicability of flexible plasmonic patches for the selective assay of fentanyl at picogram/milliliter concentration levels from drug-of-abuse patients' blood plasma. The fentanyl concentration determined in the patients' blood plasma from SERS analysis is in excellent agreement with the values determined by paper spray ionization mass spectrometry technique. We believe that the flexible plasmonic patch fabrication strategy would be widely applicable to any plasmonic nanostructures for SERS-based chemical sensing for clinical toxicology and therapeutic drug monitoring.

The localized surface plasmon resonance (LSPR) properties of nanocrystals (NCs) allow manipulation of optical responses by controlling their morphology, free carrier density, and local dielectric environment. In this context, semiconductor NCs, in which plasmonic properties arise due to various types of doping, provide unique opportunities in tailoring LSPR properties for a wide range of applications as viable alternatives to expensive noble metal NCs. Although extensive works have been done to control the LSPR properties of semiconductor NCs via doping, the role of surface ligand chemistry in the enhancement of LSPR properties remains poorly understood. Incomplete passivation of surface atoms creates dangling bonds and surface trap states that together could compromise the free carrier density and thus optoelectronic properties. Here, we report the impact of metal–ligand bonding interactions on the free electron density (N e) and the LSPR response of monoclinic, sub-stoichiometric, and two-dimensional tungsten oxide (WO3–x ) nanoplatelets (NPLs). The LSPR properties of WO3–x NPLs arise from the presence of free electrons in the conduction band as a result of oxygen vacancies in the monoclinic crystal. In situ surface passivation of unpurified colloidal WO3–x NPLs with X-type alkylphosphonate (R-PO3 2–) produces an LSPR peak in the near-infrared region of the electromagnetic spectrum. X-ray photoelectron, electron paramagnetic, and Raman spectroscopic data support the presence of a tridentate PO3–W3 bonding motif that allows increased passivation of shallow surface trap states, leading to an experimentally determined N e value of 8.4 × 1022 cm–3. Furthermore, experimentally determined bonding characteristics are correlated with density functional theory calculations. The effect of the high N e values of NPLs on their refractive index sensitivity is also evaluated. Together, the knowledge gained regarding surface-ligand-chemistry-controlled manipulation of the plasmonic properties in semiconducting metal oxide NPLs and the high N e values of WO3–x NPLs achieved may result in sizable advancement in various LSPR-driven applications such as sensing and energy storage and conversion schemes.

Nanoplasmonic superlattice surface-enhanced Raman scattering substrates have been developed for an ultrasensitive detection of fentanyl and cocaine from patients’ plasma.

Modulating optoelectronic properties of inorganic nanostructures tethered with light-responsive molecular switches by their conformational change in the solid state is fundamentally important for advanced nanoscale-device fabrication, specifically in biosensing applications. Herein, we present an entirely new solid-state design approach employing the light-induced reversible conformational change of spiropyran (SP)-merocyanine (MC) covalently attached to gold triangular nanoprisms (Au TNPs) via alkylthiolate self-assembled monolayers to produce a large localized surface plasmon resonance response (∼24 nm). This shift is consistent with the increase in thickness of the local dielectric shell-surrounded TNPs and perhaps short-range dipole−dipole (permanent and induced) interactions between TNPs and the zwitterionic MC form. Water contact angle measurement and Raman spectroscopy characterization unequivocally prove the formation of a stable TNP-MC structural motif. Utilizing this form, we fabricated the first adaptable nanoplasmonic biosensor, which uses an identical structural motif for ultrasensitive, highly specific, and programmable detection of microRNAs and proteins at attomolar concentrations in standard human plasma and urine samples, and at femtomolar concentrations from bladder cancer patient plasma (n = 10) and urine (n = 10), respectively. Most importantly, the TNP-MC structural motif displays a strong binding affinity with receptor molecules (i.e., single-stranded DNA and antibody) producing a highly stable biosensor. Taken together, the TNP-MC structural motif represents a multifunctional super biosensor with the potential to expand clinical diagnostics through simplifying biosensor design and providing highly accurate disease diagnosis.

MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in modulating gene expression and are enriched in cell-derived extracellular vesicles (EVs). We investigated whether miRNAs from human islets and islet-derived EVs could provide insight into β cell stress pathways activated during type 1 diabetes (T1D) evolution, therefore serving as potential disease biomarkers. We treated human islets from 10 cadaveric donors with IL-1β and IFN-γ to model T1D ex vivo. MicroRNAs were isolated from islets and islet-derived EVs, and small RNA sequencing was performed. We found 20 and 14 differentially expressed (DE) miRNAs in cytokine- versus control-treated islets and EVs, respectively. Interestingly, the miRNAs found in EVs were mostly different from those found in islets. Only two miRNAs, miR-155-5p and miR-146a-5p, were upregulated in both islets and EVs, suggesting selective sorting of miRNAs into EVs. We used machine learning algorithms to rank DE EV-associated miRNAs, and developed custom label-free Localized Surface Plasmon Resonance-based biosensors to measure top ranked EVs in human plasma. Results from this analysis revealed that miR-155, miR-146, miR-30c, and miR-802 were upregulated and miR-124-3p was downregulated in plasma-derived EVs from children with recent-onset T1D. In addition, miR-146 and miR-30c were upregulated in plasma-derived EVs of autoantibody positive (AAb+) children compared to matched non-diabetic controls, while miR-124 was downregulated in both T1D and AAb+ groups. Furthermore, single-molecule fluorescence in situ hybridization confirmed increased expression of the most highly upregulated islet miRNA, miR-155, in pancreatic sections from organ donors with AAb+ and T1D.