In combining DNA nanotechnology and high-bandwidth single-molecule detection in nanopipettes, we demonstrate an all-electric, label-free hybridisation sensor for short DNA sequences ({\textless} 100 nt). Such short fragments are known to occur as circulating cell-free DNA in various bodily fluids, such as blood plasma and saliva, and have been identified as disease markers for cancer and infectious diseases. To this end, we use as a model system a 88-mer target from the RV1910c gene in Mycobacterium tuberculosis that is associated with antibiotic (isoniazid) resistance in TB. Upon binding to short probes attached to long carrier DNA, we show that resistive pulse sensing in nanopipettes is capable of identifying rather subtle structural differences, such as the hybridisation state of the probes, in a statistically robust manner. With significant potential towards multiplexing and high-throughput analysis, our study points towards a new, single-molecule DNA assay technology that is fast, easy to use and compatible with point of care environments. Nanopore devices are a new class of stochastic single-molecule sensors. As nanoscale analogues of the well-known Coulter counter, which is routinely used for cell counting in hospital environments, they have been developed towards fast and label-free DNA sequencing. 1 This feat has now largely been achieved with (modified) biological pores, such as -hemolysin. 2 However, resistive pulse sensing with solid-state nanopores and nanopipettes offers a range of other potential applications. These nanodevices are relatively easy to fabricate (especially nanopipettes 3,4) and there is usually considerable flexibility in their design, with regards to the pore dimensions (diameter, channel length,

Experimental scalability of junction properties, in combination with theoretical transmission probability, demonstrates a significantly enhanced molecular connection.

The quantum-mechanical tunnelling effect allows charge transport across nanometre-scale gaps between conducting electrodes. Application of a voltage between these electrodes leads to a measurable tunnelling current, which is highly sensitive to the gap size, the voltage applied and the medium in the gap. Applied to liquid environments, this offers interesting prospects of using tunnelling currents as a sensitive tool to study fundamental interfacial processes, to probe chemical reactions at the single-molecule level and to analyse the composition of biopolymers such as DNA, RNA or proteins. This offers the possibility of a new class of sensor devices with unique capabilities.