Comprehensive landscape of small non-coding RNAs in large and small extracellular vesicles from human serum and plasma

Small non-coding RNAs (ncRNAs) are functional molecules contained within extracellular vesicles (EVs) that modulate various physiological and pathological processes. This study provides a comprehensive expression profile of seven types of small ncRNAs in serum- and plasma-derived EVs under various conditions. Both large EVs (lEVs) and small EVs (sEVs) contain high proportions of miRNAs (∼28.2% in lEVs and ∼20.8% in sEVs) and ribosomal RNAs (∼24.0% in lEVs and ∼19.1% in sEVs). lEVs are enriched with more transfer RNA (∼38.8%) than sEVs, whereas sEVs have a greater abundance of Y RNA (∼22.5%). Notably, Y RNA is more abundant in sEVs obtained from aged samples (age ≥60 years), a pattern not observed in lEVs. Small ncRNAs are more diverse in serum-derived EVs than plasma-derived EVs. There is also a high degree of overlap (>50%) in the top 100 small ncRNAs identified in lEVs and sEVs. The miRNAs hsa-miR-16-5p, hsa-let-7a-5p, hsa-miR-142-3p, and hsa-miR-103-3p are consistently among the top 10 highly expressed small ncRNAs in plasma- and serum-derived lEVs as well as in peripheral blood mononuclear cells. Serum-derived sEVs in glioblastoma, breast cancer, prostate cancer, and gastric cancer contain specific, highly expressed miRNAs, snoRNAs, small nuclear RNAs, and piRNAs. These results elucidate the patterns of small ncRNA cargoes within lEVs and sEVs derived from serum and plasma under various physiological and pathological conditions and offer valuable insights for future diagnostic and therapeutic applications.