Principles of cell and tissue organization


Identification of siRNA delivery enhancers by a chemical library screen

In this study we performed a compound library screen on two well-established siRNA delivery systems, lipid nanoparticles (LNPs) and cholesterol conjugated-siRNAs. We identified fifty-one enhancers improving gene silencing by 2 to 5 fold. Strikingly, most enhancers displayed specificity for one delivery system only. By a combination of quantitative fluorescence and electron microscopy we found that the enhancers substantially differed in their mechanism of action, increasing either the endocytic uptake or release of siRNAs from endosomes. Furthermore, they acted either on the delivery system itself or the cell, by modulating the endocytic system via distinct mechanisms. Interestingly, several compounds displayed activity on different cell types. As proof of principle, we showed that one compound enhanced siRNA delivery in primary endothelial cells in vitro and in the endocardium in the mouse heart. This study suggests that a pharmacological approach can improve the delivery of siRNAs in a system-specific fashion, by exploiting distinct mechanisms and acting upon multiple cell types. This work was achieved through a collaboration with Alnylam pharmaceuticals. Read more about this study here


Zerial lab