Previously, we have
demonstrated native mass spectrometry imaging
(native MSI) in which the spatial distribution of proteins maintained
in their native-like, folded conformations was determined using liquid
extraction surface analysis (LESA). While providing an excellent testbed
for proof of principle, the spatial resolution of LESA is currently
limited for imaging primarily by the physical size of the sampling
pipette tip. Here, we report the adoption of nanospray-desorption
electrospray ionization (nano-DESI) for native MSI, delivering substantial
improvements in resolution versus native LESA MSI. In addition, native
nano-DESI may be used for location-targeted top–down proteomics
analysis directly from tissue. Proteins, including a homodimeric complex
not previously detected by native MSI, were identified through a combination
of collisional activation, high-resolution MS and proton transfer
charge reduction.