(16a) Lipid-like Materials for RNA Delivery: A How-to Guide for Hacking Gene Expression

Despite the promise of RNA therapeutics, progress towards the clinic has been slowed by the difficulty of delivering RNA drugs, such as short interfering RNA (siRNA) and messenger RNA (mRNA), into cellular targets within the body. RNA therapeutics are large (10⁴ – 10⁶ g/mol) and negatively charged; they do not have favorable biodistribution properties in vivo nor an ability to cross the cellular membrane of target cells. In response to these challenges, our lab has created and tested large libraries of biodegradable lipid-like materials called ‘lipidoids’ using high-throughput methodologies. Lipidoids are able to efficiently manipulate gene expression in a variety of biological systems, including hepatocytes, white blood cells and tumors. Furthermore, structure-function analysis has revealed material design criteria that reliably predict in vivo delivery efficacy without the need for any biological testing. Current efforts focused on extending lipidoid delivery capabilities to mRNA will be discussed.