Small extracellular vesicle-associated surface protein biomarkers: emerging roles, opportunities, and challenges in diagnostics

Thi Thanh Huong Pham¹Hiroaki Sakamoto²Tatsuhito Hasegawa²Chisato Sakamoto²Shin-ichiro Suye²Han-Sheng Chuang^1,3*

• ¹Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
• ²Fukui Daigaku, Fukui, Japan
• ³National Cheng Kung University Hospital Medical Device Innovation Center, Tainan City, Taiwan

Investigation into the use of small extracellular vesicles (sEVs) or the specific subtype exosomes as diagnostic markers has been growing in both research output and market potential, especially in recent years. Despite these ongoing efforts, there is a lack of understanding of the value of sEV surface protein biomarkers beyond just generic tetraspanins as detected analytes in liquid biopsy. While sEV-encapsulated biomolecules, such as nucleic acids or soluble proteins, have been rigorously studied, dependence on sEV lysis would compromise the sensing robustness and diagnostic efficiency. This review article provides a comprehensive overview of sEV transmembrane proteomic signatures and highlights state-of-the-art sensors aiming towards the goal of early diagnosis and clinical monitoring of disease-associated exosomal surface protein markers.