A thermal perspective on MALDI ionization: A long journey from fundamental mechanisms to a practical solution for carbohydrate analysis

Abstract

Matrix-assisted laser desorption/ionization (MALDI) is a vital analytical tool, but the fundamental ionization mechanism has long been debated. This perspective summarizes over a decade of research to introduce a comprehensive thermal framework, culminating in the quantitative thermally induced proton transfer (TIPT) model for MALDI. Validated by numerous experiments without fitting parameters, we identify that laser-induced temperature is the dominant factor in the primary ionization of protonated ions. The principle was subsequently applied to resolve the longstanding challenges of carbohydrate analysis. To overcome the characteristically low sensitivity of carbohydrates, the rapidly freeze-drying droplet (RFDD) sample preparation method was developed by preserving homogeneously distributed, preformed sodium adducts. RFDD increases ion intensity by over two orders of magnitude, eliminates the "sweet spot" effect, and enables reliable quantitative analysis. This journey from fundamental mechanistic inquiry to a practical, innovative technology powerfully illustrates how basic science drives analytical advancements.