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Simple and fast detection of small molecules is critical for health and environmental monitoring. Methods for chemical detection often use mass spectrometers or enzymes; the former relies on expensive equipment, and the latter is limited to those that can act as enzyme substrates. Affinity reagents like antibodies can target a variety of small-molecule analytes, but the detection requires the successful design of chemically conjugated targets or analogs for competitive binding assays. Here, we developed a generalizable method for the highly sensitive and specific in-solution detection of small molecules, using cannabidiol (CBD) as an example. Our sensing platform uses gold nanoparticles (AuNPs) functionalized with a pair of chemically induced dimerization (CID) nanobody binders (nanobinders), where CID triggers AuNP aggregation and sedimentation in the presence of CBD. Despite moderate binding affinities of the two nanobinders to CBD (equilibrium dissociation constants KD of ∼6 and ∼56 μM), a scheme consisting of CBD−AuNP preanalytical incubation, centrifugation, and electronic detection (ICED) was devised to demonstrate a high sensitivity (limit of detection of ∼100 picomolar) in urine and saliva, a relatively short sensing time (∼2 h), a large dynamic range (5 logs), and a sufficiently high specificity to differentiate CBD from its analog, tetrahydrocannabinol. The high sensing performance was achieved with the multivalency of AuNP sensing, the ICED scheme that increases analyte concentrations in a small assay volume, and a portable electronic detector. This sensing system is readily applicable for wide molecular diagnostic applications. 

Solid-state nanopore sensors have broad applications from single-molecule biosensing to diagnostics and sequencing. Prevalent nanopore sensors are fabricated on silicon (Si) substrates through micromachining, however, the high capacitive noise resulting from Si conductivity has seriously limited both their sensing accuracy and recording speed. A new approach is proposed here for forming nanopore membranes on insulating sapphire wafers by anisotropic wet etching of sapphire through micro-patterned triangular masks. Reproducible formation of small membranes with an average dimension of ~10 μm are demonstrated. For validation, a sapphire-supported (SaS) nanopore chip, with a 100 times larger membrane area than silicon-supported (SiS) nanopore, showed 130 times smaller capacitance (10 pF) and ~2.5 times smaller rootmean-square (RMS) noise current (~20 pA over 100 kHz bandwidth). Tested with 1k bp double-stranded DNA, the SaS nanopore enabled sensing at microsecond speed with a signal-to-noise ratio of 21, compared to 11 from a SiS nanopore. This SaS nanopore presents a manufacturable platform feasible for biosensing as well as a wide variety of MEMS applications.