Enhancing siRNA delivery by employing lipid nanoparticles

For several decades extensive research has been conducted into the development of fusogenic lipid nanoparticles (LNPs) capable of introducing large, charged molecules into the cytoplasm of target cells. The majority of this work has focused on cationic LNPs encapsulating nucleic acids ranging from small oligonucleotides to large plasmid constructs thousands of bases long. However, since the introduction of siRNA payloads this quest for a non-viral, intracellular delivery systems has advanced significantly. Of particular importance was the demonstration that LNPs containing ionizable, dialkylamino lipids, enable potent hepatic gene silencing across species including humans. This review focuses on the evolution of this delivery system, summarizes the promising data now emerging from clinical trials and considers future directions for the platform.