Charge Detection-MS: Opening a New Frontier of Mass Spectrometry

Techniques for the detection of extremely high mass ions or the analysis of heterogenous samples in mass spectrometry are often limited by overlapping charge states and poor resolution.¹ The invention of electrospray ionization allowed for ionization of increasingly larger ions in mass spectrometry where multiple charging allows for the mass-to-charge ratio to be much lower than the molecular mass.² In traditional mass spectrometry, the mass-to-charge ratio is measured and then the charge of the ion is deduced from the spacing of isotope peaks. Charge detection mass spectrometry (CD-MS) is a recently developed technique in which the charge and mass of a singular ion are measured simultaneously.³ CD-MS performance is limited by a dependence on initial ion trajectory/conditions, charge detection uncertainty, ion loss, and long acquisition times. CD-MS has already found uses analyzing large adenovirus complexes above 150 MDa to investigate lot to lot variability.⁴ Charge detection mass spectrometry opens new frontiers in mass spectrometry by raising the upper mass limit potentially into the gigadalton range.¹

(1) Todd, A. R.; Barnes, L. F.; Young, K.; Zlotnick, A.; Jarrold, M. F. Higher Resolution Charge Detection Mass Spectrometry. Anal Chem 2020, 92 (16), 11357–11364. DOI: 10.1021/acs.analchem.0c02133

(2) Strasser, L.; Fussl, F.; Morgan, T. E.; Carillo, S.; Bones, J. Exploring Charge-Detection Mass Spectrometry on Chromatographic Time Scales. Anal Chem 2023, 95 (40), 15118–15124. DOI: 10.1021/acs.analchem.3c03325

(3) Jarrold, M. F. Single-Ion Mass Spectrometry for Heterogeneous and High Molecular Weight Samples. J Am Chem Soc 2024, 146 (9), 5749–5758. DOI: https://doi.org/10.1021/jacs.3c08139

(4) Kontogiannis, T.; Braybrook, J.; McElroy, C.; Foy, C.; Whale, A. S.; Quaglia, M.; Smales, C. M. Characterization of AAV vectors: A review of analytical techniques and critical quality attributes. Mol Ther Methods Clin Dev 2024, 32 (3), 101309. DOI: https://doi.org/10.1016/j.omtm.2024.101309.