A novel gemini-like cationic lipid for the efficient delivery of siRNA

Although RNAi is a promising strategy for the intervention of human diseases, an essential prerequisite is the development of low-toxic and efficient siRNA delivery systems. In this report, we describe a novel gemini-like cationic lipid (CLD) that was developed and evaluated for the delivery of siRNA. The novel lipid contains a disulfide bond in the spacer, which can be cleaved under reductive conditions in the cytoplasm and decrease lipid toxicity. The liposomes formed by CLD exhibited a high siRNA binding property, which was facilitated by the increased number of cationic charges. Moreover, the cationic lipids showed low cytotoxicity. They protected siRNAs from degradation by nucleases and the complexed siRNA was released efficiently in the presence of low concentrations of polyanionic heparin. High content screening and confocal microscopy studies demonstrated that lipoplexes with FAM labeled siRNA showed efficient cell uptake by HeLa and A375 cells. Finally, siRNA targeting MEK1 mRNA formulated in liposomes demonstrated effective endosomal escape after cellular uptake and efficient gene silencing of MEK1 expression. These results demonstrated the promising use of the novel gemini-like cationic lipid for the efficient and safe delivery of siRNA.