ZnS/Au Composites Advance Comprehensive Characterization of Low‐Molecular‐Weight Compounds Toward Pharmaceutical Analysis of Traditional Chinese Medicine

ABSTRACT Low‐molecular‐weight (LMW) compounds, including both endogenous and exogenous molecules, are critical in characterizing diverse life processes, such as cancer. Specifically, the comprehensive characterization of LMW compounds aids in understanding the pharmacological effects of traditional Chinese medicine (TCM), enabling the identification of active ingredients and assessment of therapeutic efficacy against tumor cells. However, challenges arise in laser desorption/ionization mass spectrometry (LDI MS) due to the limited availability of existing matrices and the detection preference for specific molecules. Here, ZnS/Au (ZA) composites are developed as matrices for LDI MS, achieving a 100% detection coverage of 78 standard analytes in dual‐ion modes. The composites are optimized with a loose ZnS substrate densely anchored with large Au nanoparticles, forming a Schottky heterostructure at the interface. This design results in the generation of stable hotspot layers and long‐lifetime electron‐hole pairs. Consequently, a wide coverage of phytochemicals (12 categories, 50 types) is identified from 11 TCMs. Further, the growth‐inhibitory of TCMs on A549 lung cancer cells are validated based on metabolic profiles of endogenous molecules. This study provides an efficient tool to elucidate the active components and action mechanisms of the complex TCM system at the molecular level, thereby advancing the modernization and standardization of TCM.