Single-Molecule Sensitivity in Mass Spectrometry Using Nanoscale Ion Sources*

Electrospray ionization has revolutionized the analysis of biomolecules by softly transforming molecules in solution into gas-phase ions, which can be analyzed by mass-spectrometry. Due to the chaotic process by which the electrosprayed droplets break down into ever-smaller droplets, eventually yielding singly charged ions via ion evaporation, only a small fraction of the sample molecules makes it to the mass analyzer. We have shown that a nanoscale ion source allows ions to evaporate directly off of the meniscus, bypassing the wasteful droplet evaporation process. The small area of the liquid-vacuum interface also prevents significant evaporative heat loss, enabling the use of volatile solvents like water. This technique has been shown to work with simple salt solutions as well as aqueous solutions of biomolecules such as amino acids, nucleic acids, and small peptides. Adoption of these nanopore ion sources could drastically improve the sensitivity of mass spectrometry experiments and open the door to a wide range of potential applications, including single-molecule protein sequencing and single cell proteomic studies.