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

Abstract 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 (^HBEV‐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 ^HBEV‐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.