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We describe the DRILL (dry ion localization and locomotion) device, which is an interface for electrospray ionization (ESI)-mass spectrometry (MS) that exploits a swirling flow to enable the use of inertial separation to prescribe different fates for electrosprayed droplets based on their size. This source adds a new approach to charged droplet trajectory manipulation which, when combined with hydrodynamic drag forces and electric field forces, provides a rich range of possible DRILL operational modes. Here, we experimentally demonstrate sensitivity improvement obtained via vortex-induced inertial sorting of electrosprayed droplets/ions: one possible mode of DRILL operation. In this mode, DRILL removes larger droplets while accelerating the remainder of the ESI plume, producing a high velocity stream of gas-enriched spray with small, highly charged droplets and ions and directing it toward the MS inlet. The improved signal-to-noise ratio (10-fold enhancement) in the detection of angiotensin I is demonstrated using the DRILL interface coupled to ESI-MS along with an improved limit of detection (10-fold enhancement, 100 picomole) in the detection of angiotensin II. The utility of DRILL has also been demonstrated by liquid chromatography (LC)-MS: a stable isotope labeled peptide cocktail was spiked into a complex native tissue extract and quantified by unscheduled multiple reaction monitoring on a TSQ Vantage. DRILL demonstrated improved signal strength (up to a 700-fold) for 8 out of 9 peptides and had no effects on the peak shape of the transitions. [ABSTRACT FROM AUTHOR]