Spatially-resolved chemical profiling of substructures in biological tissues has attracted great attention. The abundance of proteins as the effector molecules plays an important role in the biological functions that vary across tissue space. Our group uses top-down mass spectrometry to image intact proteoforms from tissues with molecular specificity to identify posttranslational modifications and sequence variations. Recently we developed proteoform imaging mass spectrometry (PiMS), which combines a sensitive localized sampling probe, nanospray desorption electrospray ionization (nano-DESI), with ion detection using individual ion mass spectrometry (I<sup>2</sup>MS). PiMS was first applied to human kidney tissues to enable imaging and identification of proteoforms up to 70 kDa and &lt;1% dynamic range. Next, we aim to understand the limit of the detection of proteoform in tissue. To achieve this goal, we designed and fabricated a high spatial resolution nano-DESI probe using pulled capillaries, with allows for the detection of proteoform features &lt;0.1% relative abundance. Moreover, the setup achieved spatial resolution &lt;10 µm providing a highly-localized sampling of single cells from tissue sections. Using this high-resolution probe, we were able to detect proteoforms at attomole scale sensitivity. With this new PiMS technology, we hope to obtain a proteoform-level understanding of spatial biology at single-cell resolution.

Attomole-sensitivity source for tissue imaging of large-molecules

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