Nanomatrix engineering for LDI-MS based biomedical metabolomics

Metabolomics provides functional molecular readouts of disease phenotypes, therapeutic responses, and tissue microenvironments, but its extension to low-volume, single-cell, and spatially resolved samples remains analytically challenging. Laser desorption/ionization mass spectrometry (LDI-MS) offers a rapid, direct, and high-throughput route for small-molecule analysis. However, its performance in biomedical metabolomics is largely governed by the matrix-analyte interface. Nanomaterials have emerged as attractive LDI-MS matrices because of their low background in the low-mass region, large surface area, tunable photothermal and electronic properties, and designable surface chemistry. In this review, we summarize recent advances in nanomatrix-assisted LDI-MS for biomedical metabolomics, emphasizing design principles. We discuss three key design dimensions of nanomatrix and interface engineering: structural engineering for energy absorption and desorption efficiency, surface functionalization for metabolite enrichment and low-interference ionization, and interface engineering for reproducibility, throughput, and low-volume sample compatibility. Representative biomedical applications are highlighted, including biofluid metabolic fingerprinting, extracellular vesicle and single-cell metabolomics, and spatial metabolic imaging. Finally, we discuss current challenges in matrix reproducibility, metabolite coverage, workflow standardization, and clinical validation, and outline future opportunities for integrated nanomatrix platforms in multiscale biomedical metabolomics.