Cysteine/GSH-Responsive Lipid Switch Development for Liposome Triggered Cargo Release

Liposomal delivery has emerged as an effective way to transport a broad range of therapeutics due to the excellent biocompatibility of these nanocarriers and their capacity to encapsulate a wide variety of cargo. However, challenges still persist in controlled content release at diseased cells. Although several stimuli have been recently targeted to achieve effective liposomal triggered release at the target site, cysteine and glutathione (GSH), which are overabundant in cancer cells and play crucial roles by deterring oxidative stress and enhancing cell survival offer important targets. Here, we introduce a unique cysteine/GSH-responsive liposomal platform, which was achieved by incorporating a newly developed SLPC lipid containing a disulfide moiety inserted within the sn-2 acyl chain. Förster Resonance Energy Transfer (FRET)-based fluorescence assays, transmission electron microscopy, and dynamic light scattering studies confirmed the formation of stable spherical liposome vesicles containing our SLPC lipid switch and cysteine-responsive controlled cargo release. Selectivity screening with cysteine, GSH, homocysteine, dithiothreitol, methionine, serine, glutathione disulfide (GSSG), alanine, and glutamate demonstrated that SLPC-containing liposomes show a triggered response only in the presence of molecules containing active thiols. These findings demonstrate that SLPC can act as a potent liposomal platform to achieve cysteine/GSH-triggered controlled content release toward the goal of targeted drug delivery to diseased cells.