Lipidome Analysis of Cancer Cells and Their Extracellular Vesicles Reveals Cancer‐Type‐Specific Lipid Signatures and Enables the Design of EV‐Mimetic Liposomes

Lipid metabolism reprogramming is a hallmark of cancer, yet the global lipidome of cancer cells and their extracellular vesicles (EVs) remains poorly understood. Using mass spectrometry, we analyzed the lipid profiles of a panel of human cancer and non-cancer cell lines along with their secreted EVs. Cancer cells exhibited distinct lipid signatures, including elevated lipid raft components. Cancer-derived EVs displayed unique lipid compositions that clustered separately from cell lipid profiles, suggesting active lipid sorting during EV biogenesis. Comparative analysis of primary and metastatic cells and their EVs, highlighted phospholipid alterations during metastasis. These findings suggest that EV lipid profiles could serve as cancer biomarkers, and the data can inform synthetic EV-based nanoparticle design for drug delivery. Our study provides one of the most comprehensive characterizations of the cancer EV lipidome to date, offering novel insights into lipid metabolism in cancer progression and potential therapeutic applications.