Complex RNA world in small extracellular vesicles for liquid biopsy in cancer management

Liquid biopsy is a valuable tool in oncology with its advantages of non-invasiveness, longitudinal sampling, and capturing the intra- and inter-tumor heterogeneity. Small extracellular vesicles (sEVs) are released by cells into various biological fluids, providing a window to ascertain the cellular status of the source cells. Although many aspects of sEV biology are still enigmatic, analysis of sEV contents in biofluids offers readouts with broad applications, and may be superior or complementary to other assays of liquid biopsy. sEVs carry cell-derived biomaterials, including nucleic acids, proteins, lipids, and metabolites. RNAs are dominant components packed in sEVs, consisting of various biotypes. Protected by the phospholipid bilayer outer membrane of the sEVs, sEV RNAs are remarkably stable. Therefore, the RNA cargos originated from the cancer cells might have high potential as biomarkers in analysis of oncological features. This review will (1) characterize the RNA species loaded into sEVs as well as the related RNA metabolism; (2) summarize the molecular mechanisms of RNA sorting into sEVs, and (3) discuss the potential of using liquid biopsy of sEV RNAs in oncology for early diagnosis of tumor, assessment of tumor burden, response to therapy and monitoring minimal residual disease for recurrence and disease progression.