The overarching goal of this proposal is to develop a novel atmospheric pressure droplet desolvation/ ion collection interface for efficient delivery of softly ionized biomolecules to mass analyzers, which will dramatically improve sensitivity and dynamic range of mass spectrometry (MS) for complex biochemical samples. Such an interface is a critical enabling technology for raising MS capability to the next level, and to further advance this key tool in health related sciences, including applications to proteomics, metabolomics, biomarker discovery and drug development. An interdisciplinary research team comprised of a bioengineer, an analytical chemist, and a proteomics scientist will develop, demonstrate and optimize the novel interface system, DRILL (DRy Ion Localization and Locomotion), for ESI LC-MS workflows with a number of unique capabilities, using a multifaceted approach that combines innovative engineering design, supported by powerful electrohydrodynamics analysis, simulation and experiments, advanced DOE (design of experiment) analytical characterization methodology, and state-of-the-art applications to challenging proteomics problems. With an optimally-designed DRILL desolvation and ion transport interface, we aim to eliminate ion losses due to incomplete desolvation (including signal suppression) and inefficient ion collection, and to enable a dramatic improvement in sensitivity and dynamic range of detection as compared to the current state of the art. The research team members are well situated to meet the scientific and engineering challenges associated with addressing the need for an improved MS interface, with a track record of successful research on ion sources, bio-analytical devices and sensors, mass spectrometry, proteomics and interdisciplinary collaboration. As a result of this work, the research team will have completed all steps necessary to make the proposed DRILL system a widely applicable tool for biological and clinical researchers, aiming to improve current MS performance and to develop new MS applications for both top-down and bottom-up proteomics. Broad dissemination to enhance scientific and technological understanding will be achieved through several activities. In particular, the research results will be communicated through technical papers and presentations in scientific forums, developing an online resource summarizing the design and operation guidelines for DRILL device operation and enabled new LC-MS workflows, as well as special events (hands-on training workshops for clinical practitioners) that the research team plans to organize.