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Glass nanopipette has gained widespread use as a versatile single-entity detector in chemical and biological sensing, analysis, and imaging. Its advantages include low cost, easy accessibility, simplicity of use, and high versatility. However, conventional nanopipettes based on the volume exclusion mechanism have limitations in detecting small biomolecules due to their small volume and high mobility in aqueous solution. To overcome this challenge, we have employed a novel approach by capitalizing on the strong nanoconfinement effect of nanopipette. This is achieved by utilizing both the hard confinement provided by the long taper nanopipette tip at the cis side and the soft confinement offered by the hydrogel at the trans side. Through this approach we have effectively slowed down the exit motion of small molecules, allowing us to enrich and jam them at the nanopipette tip. Consequently, we have achieved high throughput detection of small biomolecules with sizes as small as 1 nm, including nucleoside triphosphates, short peptides, and small proteins with excellent signal-to-noise ratios. Furthermore, molecular complex formation through specific intermolecular interactions, such as hydrogen bonding between closely spaced nucleotides in the jam-packed nanopipette tip, have been detected based on the unique ionic current changes. 

Single-entity electrochemistry is of fundamental importance and shows promise for ultrasensitive biosensing applications. Recently, we have demonstrated that various charged nanoparticles can be detected individually based on the non-redox open-circuit potential (OCP) changes induced by their collision events on a floating carbon nanoelectrode (CNE). Unlike the widely used amperometry approach, the potentiometric method provides the label-free detection of individual nanoscale entities without redox mediators in the solution. However, the CNE lacks specificity for molecular recognition during the collision events because of the limited methods of surface functionalization for carbon surfaces. Herein, we used surface-functionalized gold nanoelectrode (GNE) to overcome this limitation of CNE. The GNE modified with Raman reporter molecule also enabled surface-enhanced Raman spectroscopy (SERS) measurements. By using simultaneous time-resolved OCP and SERS measurements, both the OCP and SERS signals induced by the “hit-n-run” type of gold nanoparticle (GNP) collision events can be better understood. Also, by introducing a zwitterionic molecule, we formed near “stealth” surface and demonstrated that the non-specific adsorptions of GNPs to the surface of GNE have been suppressed, allowing continuous detection of hit-n-run events for over 30 min.