WHAT IT IS
Charge Detection Mass Spectrometry (CDMS) is a form of mass spectrometry that measures, for each individual ion, both its mass-to-charge ratio (m/z) and its absolute charge (z). The true mass is then obtained directly:
m=(m/z)
This makes CDMS uniquely suited for very large and heterogeneous species where conventional MS cannot resolve charge states or isotopic patterns such as viral vectors, plasmid DNA, virus-like particles, and large protein complexes.
Next-generation CDMS systems are positioning this technique as a routine tool for “mega-mass” biomolecules, complementing standard LC–MS in advanced biopharma and structural biology workflows.
HOW IT WORKS
Ionization – Typically native or near-native nano-ESI in volatile buffers produces multiply charged macromolecular ions.
Single-Ion Regime – Ion optics and automatic ion control (AIC) limit the number of ions entering the analyzer so that most transients contain one (or very few) ions.
Trapping & Detection – In an electrostatic or Orbitrap-type trap, each ion oscillates and induces a tiny image current in the detection electrodes.
Frequency → m/z
Signal amplitude / slope → charge (z) via calibration
Mass Reconstruction – Thousands of individual ion events are combined into a true mass spectrum directly in the mass domain, without deconvolution.
ADVANTAGES
Direct mega-mass measurement – Accurate masses for ions in the MDa range, far beyond routine MS.
Handles extreme heterogeneity – Works when charge states overlap or when intact LC–MS spectra are too congested (e.g., heavily glycosylated biotherapeutics).
Single-particle insight – Reveals mass distributions, subpopulations, and rare species (e.g., partially filled viral capsids).
LC compatibility – SEC–CDMS separates components, reduces matrix effects, and supports automated, chromatographic workflows.
Lower need for deconvolution – Mass is calculated per ion, avoiding complex charge-state modeling.
CHALLENGES AND LIMITATIONS
Lower throughput than ensemble MS – Single-ion operation and the need for many spectra per mass distribution slow analysis.
Method complexity – Requires careful tuning of ion flux, transient length, and AIC to avoid multi-ion events and frequency shifts.
Data processing load – Charge calibration and individual-ion signal processing are more demanding than standard deconvolution.
Limited fine isoform detail at LC time scales – On short peaks, CDMS typically reports dominant masses and overall heterogeneity rather than a fully resolved glycoform catalog.
TYPICAL APPLICATIONS
Gene-therapy vectors – Determining empty/partial/full ratios of rAAV capsids; assessing packaging heterogeneity.
Plasmid DNA – Checking integrity, size distributions, and truncations in gene-therapy plasmids.
Virus-like particles (VLPs) – Characterizing VLP vaccines (e.g., chikungunya, hepatitis B).
Complex glycoproteins and Fc-fusion biotherapeutics – Intact mass and heterogeneity assessment where conventional LC–MS fails to cleanly resolve charge states.
Large protein assemblies – Native analysis of proteasomes, ribosomes, and other macromolecular complexes, clarifying stoichiometry and assembly states.