Low-Noise Nanopore Enables In-Situ and Label-Free Tracking of a Trigger-Induced DNA Molecular Machine at the Single-Molecular Level.

Solid-state nanopores have shown special high potential in a label-free molecular assay, structure identification, and target-index at the single-molecular level, even though frustrating electrical baseline noise is still one of the major factors that limit the spatial resolution and signaling reliability of solid-state nanopores, especially in small target detection. Here we develop a significant and easy-operating noise-reduction approach via mixing organic solvents with high dielectric constants into a traditional aqueous electrolyte. The strategy is generally effective for pores made of different materials, such as the most commonly used conical glass (CGN) or SiN. While the mechanism should be multisourced, MD simulations suggest the noise reduction may partially arise from the even ionic distribution caused by the addition of higher dielectric species. Among all solvents experimentally tested, the two with the highest dielectric constants, formamide and methylformamide, exhibit the best noise reduction effect for target detection of CGN. The power spectral density at the low-frequency limit is reduced by nearly 3 orders with the addition of 20% formamide. Our work qualifies the reliability of solid-state nanopores into much subtler scales of detection, such as dsDNAs under 100 bp. As a practical example, bare CGN is innovatively employed to perform in-situ tracking of trigger-responsive DNA machine forming oligomers.