Coulomb Field-Driven Desorption/Ionization by Femtosecond Laser for Mass Spectrometry Detection and Imaging

Surface-assisted laser desorption/ionization (SALDI) offers promising prospects for mass spectrometry detection and imaging of small biomolecules, as it addresses most of the matrix-related issues encountered in conventional matrix-assisted laser desorption/ionization (MALDI). Currently, nearly all of the fundamental aspects and applications of SALDI depend on nanosecond (ns) lasers, whereas few efforts have been made to integrate ultrafast femtosecond (fs) lasers with SALDI. Therefore, the intrinsic fundamental principle remains poorly understood. Herein, a novel surface-assisted femtosecond laser desorption/ionization mass spectrometry (fs-SALDI-MS) platform was developed, which significantly reduces analyte fragmentation and preserves molecular integrity. Spectral interferences from surface-assisted materials and alkali-metal adducts are absent in fs-SALDI mass spectra. Ion survival yields continuously increase with decreasing laser pulse widths from 5 ns to 600 fs, highlighting a gradual transition from thermal to nonthermal effects. A lower absolute limit of detection down to ∼3 amol for representative antifungal and psychotropic drugs and clearer visualization of ultratrace drug residues on latent fingerprints can be achieved, indicating that fs-SALDI results in gentler and more efficient detection/ionization processes than mainstream ns-SALDI. The biological applicability of this method was further validated through 10 μm-spatial-resolution lipid imaging of mouse brain sections. In short, a novel Coulomb field-driven desorption/ionization mechanism is proposed for fs-SALDI, opening new avenues for the development of emerging fs-SALDI techniques with superior analytical performance.