Scalable, high-purity isolation of blood extracellular vesicles via a cleavable DNA–lipid anchor

Extracellular vesicles (EVs) provide a protected molecular record of disease activity, but their potential as blood-based biomarkers has been limited by isolation methods that are slow, impure, and poorly scalable. We developed a cleavable DNA–lipid anchor (cDLA) that reframes EV isolation as a modular chemistry platform, enabling rapid, economical bead-based capture and release of intact vesicles. In plasma, cDLA achieved markedly higher purity than size-exclusion chromatography, yielding deeper proteomic coverage. We applied the approach to uncover plasma vesicular tau signals that more faithfully tracked with cerebrospinal fluid, improving diagnostic discrimination over bulk plasma tau. cDLA provides a robust and clinically scalable method for EV isolation, with broad potential for liquid biopsy in neurodegenerative disease and beyond.