Cells use lipid rafts, regions enriched in specific proteins and lipids, to control membrane receptor activation and signaling. Lipid rafts allow proteins to cluster together to properly initiate signaling and also remove other proteins that might sterically hinder protein interactions or remove inhibitory proteins. While phase separated vesicles, vesicles with a ternary mixture of saturated and unsaturated phospholipids with cholesterol, have been used as a model membrane to study lipid rafts, they have not been used extensively for controlling receptor signaling in drug delivery applications. Here, we use phase separated vesicles to enhance the signaling of TRAIL (TNF-related apoptosis inducing ligand). TRAIL induces apoptosis in cancer cells by signaling through death receptors DR4 and DR5 and has been previously shown to be enhanced by conjugation onto lipid vesicles. We demonstrate that concentrating TRAIL in the unsaturated lipid region of phase separated vesicles, thereby mimicking lipid rafts, enhances TRAIL signaling and apoptosis in Jurkat cancer cells expressing DR5. Further analysis of phase separated TRAIL vesicles against other cell types demonstrates that clustering TRAIL in lipid rafts only enhances apoptosis in cells that express more DR5 than DR4, demonstrating different signaling requirements for the two receptors. Phase separated vesicles can be used to control signaling of membrane receptors and has the potential to enhance liposome drug delivery systems.

Phase separation in lipid vesicles enhances TRAIL-mediated cytotoxicity.

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ACS Fall 2022

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