Evaluation of Surface Acoustic Wave Nebulization for NEMS Mass Spectrometry

Nano‐electromechanical systems mass spectrometry (NEMS‐MS) enables single‐particle mass measurements with resolving power that increases for ultra‐massive analytes, but its practical sensitivity is currently limited by sample introduction methods. Here, we evaluated surface acoustic wave nebulization (SAWN) as a suitable particle source for NEMS‐MS. A compact SAW‐based nebulizer was characterized using scanning mobility particle sizer (SMPS) measurements of sucrose residues, yielding a mean droplet diameter of ~2.0 μm and a transmission efficiency of up to 30%. Nebulization of solid nanoparticles was validated using polystyrene latex (PSL) standards. Application of SAWN‐NEMS‐MS to biological capsid‐like particles (CLP) revealed substantial nonvolatile salt adduction, contributing to the detected mass and broadening mass distributions. At high particle concentrations, multiparticle encapsulation produced aggregates exceeding 100 MDa. Our findings outline the potential and limitations of SAWN for single‐particle NEMS‐MS: while demonstrating enhanced transfer efficiency, our results indicate that reduced droplet sizes and extensive desalting are essential requisites for achieving native analysis of large biological assemblies.