Tim4‐Functionalized HBEV‐Chip by Isolating Plasma‐Derived Phosphatidylserine‐Positive Small Extracellular Vesicles for Pan‐Cancer Screening

Thanks to containing tumor-related molecules, small extracellular vesicles (sEVs) are emerging as biomarkers in tumor liquid biopsy and commonly employed to diagnose a specific cancer. However, a pan-cancer screening method for pre-symptomatic patients is crucial to achieving the early cancer detection. Herein, a lipid-protein capture system on herringbone (HB) microfluidic chip ((EV)-E-HB-Chips) to isolate multiple tumor-derived sEVs is constructed. Phosphatidylserine (PS) is abnormally surface-supposed on tumor-derived sEVs and binds T-cell immunoglobulin domain and mucin domain-containing protein 4 (Tim4) in calcium-dependent manner. PS+ sEVs isolated by the (EV)-E-HB-Chips is perform on liquid chromatography electrospray ionization tandem mass spectrometry and it is found that PS+ sEVs are highly correlated with tumor-related pathway (P < 0.05), such as Cdc42 protein signal transduction, neuropilin signaling pathway, and Wnt signaling pathway. And it is further validated in clinical sample and found that PS(+)sEV number shows statistical difference between cancer patients and healthy donors in plasma (P < 0.01) and has efficient diagnostic power (area under curve = 0.86), suggesting PS(+)sEV as potential biomarker for pan-cancer screening. The Tim-4 functionalized device facilitates the early multiple cancer detection, providing the potential to be used as a rapid-screening tool in clinical setting.