The present technology provides methods for increasing sensitivity of detection and/or quantification of a negatively charged analyte, e.g., an oligonucleotide, using an analytical system that comprises liquid chromatography and mass spectrometry. The methods comprise passing an acidic solution through the analytical system, i.e., through a fluidic path from the mobile phase reservoir to the detector to remove or displace, at least in part, metal ions adsorbed to charged sites in the fluidic path.

Systems and methods for delivering a sample to a mass spectrometer are provided. In one aspect, the systems and methods can provide efficient cooling of an ion source probe to prevent overheating and the resulting degradation in ion sampling. In some aspects, such cooling can result in improved consistency and/or efficiency of ion formation. Moreover, ion source cooling in accordance with various aspects of the present teachings can allow for the use of higher temperatures in the ionization chamber (thereby improving desolvation) and/or can enable the use of lower flow rate sample sources than with conventional techniques.