Cocktail Effect in High-Entropy Oxide (FeCoNiCuZn)xOy Enables Universal Metabolite Detection for LDI-MS Bioanalysis.

Surface-Assisted Laser Desorption/Ionization Mass Spectrometry (SALDI-MS) has gained considerable attention for its advantages, such as low background noise and high salt tolerance. However, developing novel matrices that simultaneously offer high sensitivity, broad universality, and excellent reproducibility remains a key challenge. In this work, high-entropy oxide nanoparticles (HEO NPs) were successfully synthesized and applied for the first time as a high-performance nanomatrix in LDI-MS detection. The HEO NPs exhibited minimal background, excellent reproducibility, and broad metabolite coverage, encompassing amino acids, organic acids, and nucleotides, while significantly outperforming conventional organic matrices and single-metal oxides. Mechanistic investigations revealed that the unique multielement "cocktail effect" in HEO optimizes their electronic band structure and surface properties. This optimization not only enhances the efficiency of photothermal conversion but also facilitates the separation and transfer of photogenerated carriers, thereby strengthening the adsorption, desorption, and ionization processes of analytes. Ultimately, the practical utility of our HEO-based LDI-MS platform was validated through its application in the discrimination of urological cancers. Coupled with an AI model, the platform enabled accurate identification among kidney, bladder, and prostate cancers (AUC > 0.97). Collectively, this research delivers a novel analytical platform that integrates superior LDI-MS performance, a well-understood synergistic mechanism, and direct clinical translational value for noninvasive metabolic diagnostics.