Hybrid Extracellular Vesicles‐Liposomes Camouflaged Magnetic Vesicles Cooperating with Bioorthogonal Click Chemistry for High‐Efficient Melanoma Circulating Tumor Cells Enrichment

Abstract The capture of melanoma circulating tumor cells (melanoma CTCs, MelCTCs) is of great significance for the early diagnosis and personalized treatment of melanoma. The rarity and heterogeneity of MelCTCs have greatly limited the development of MelCTCs capture methods, especially those based on immune/aptamer‐affinity. Herein, an extracellular vesicles‐camouflaged strategy is designed to functionalize the magnetic nanoparticles (Fe 3 O 4 ) and to generate magnetic vesicles (Fe 3 O 4 @lip/ev) with excellent antifouling and active tumor cell targeting properties. Combined with the bioorthogonal click chemistry, the engineered magnetic vesicles with dibenzocyclooctyne can be widely used to target and separate all the metabolically labeled CTCs with varied phenotypes, organ origin, and even the biological species. The capture efficiency exceeded 80% with an extremely low detection limitation of ten cells. Most importantly, the strategy proposed can be directly applied to enrich MelCTCs from 0.5 mL blood samples of melanoma‐bearing mice, with a greatly minimized residue of white blood cells (only 21–568) while ignoring the fluctuations of MelCTC phenotype.