Metabolites in Serum Small Extracellular Vesicles Instead of Small Extracellular Vesicles‐depleted Serum Have Better Diagnostic Value for Cancers at Early Stage

Abstract Serum is one of the most commonly used biofluids for biomarker exploration. Some studies examine serum directly, while others focus on specific components like small extracellular vesicles (sEVs), which are lipid‐bilayer encapsulated particles carrying a variety of molecular cargos. However, the diagnostic value of serum sEVs versus sEVs‐depleted fractions (EV‐free serum) for early cancer detection are unclear. In the study, size exclusion chromatography (SEC) is employed to separate serum from prostate cancer (PCa) suspects into sEVs‐enriched fractions (EV) and EV‐free serum. Metabolic fingerprints are obtained using ferric nanoparticle‐assisted laser ablation/ionization mass spectroscopy (FeNPALDI‐MS), revealing heterogeneity in metabolic composition. Eleven key metabolites are identified in EV and two in EV‐free serum that differentiate PCa from benign prostatic hyperplasia. The EV key metabolites showed higher diagnostic value in PCa patients with an area under the curve (AUC) of 0.76, p < 0.05 and improved diagnostic efficacy when combined with the prostate‐specific antigen (PSA, AUC = 0.85).