Abstract/Summary Over the last 20 years, mass spectrometry (MS) instrumentation has advanced at a remarkable clip. Improvements in ion focusing, mass analyzer, and ion detection regions have greatly enabled the study of protein molecules in their native state (native MS). One area that has remained relatively constant is the ionization source where nanoelectrospray ionization (nESI) has remained the most sensitive means to produce the large biomolecules of interest. A severe drawback of nESI for native MS is that it suffers from stability issues when operated in negative ion mode. This primarily results from the earlier onset of the corona discharge in negative ion mode which abrogates ion production. The result of this limitation is to drastically reduce the utility of native MS as >104 proteins exhibit PI values below 6. This has implications for the study of protein structures important to human health ranging from therapeutic molecules to those associated with disease onset and progression. Recently, the research group of Prof. Peng Li at West Virginia University developed a new ionization technique termed Vibrating Sharp-edge Spray Ionization (VSSI). The approach has recently been demonstrated to provide a 10× to 100× boost in ionization performance compared with state-of-the-art approaches operated in negative ion mode. Here, we will leverage the power of the new approach to provide a prototype ionization source which will consistently provide 100× signal enhancements in negative ion mode and 10× improvement in positive ion mode. These leaps in ionization efficiency will unlock the door to high-efficiency native MS experiments especially in negative ion mode. The result will be to enable human health researchers to characterize the structures of many important proteins that have heretofore remained largely inaccessible.