Messenger RNA (mRNA) therapeutics have taken center stage thanks to the successful deployment of the SARS-CoV2 mRNA vaccines in hundreds of millions of people worldwide. These vaccines were made possible by a herculean effort to overcome the most significant barriers that have hindered translational efforts. Arguably, the largest challenge has been that RNA molecules do not readily enter their cellular targets within the body. This is because they are large (104 – 106 g/mol) and negatively charged; they do not have favorable biodistribution properties nor an ability to cross the cell membrane of target cells. In response to these issues, industrial and academic laboratories, including my own, have created lipid nanoparticles that spontaneously package RNA and deliver the RNA to key cellular targets in vivo. Here, I will describe biodegradable, ionizable lipid-like materials called ‘lipidoids’ that my lab has used to create RNA-loaded lipid nanoparticles that induce protein expression in a variety of tissues. This talk will describe how simple changes in nanoparticle chemistry and route of administration cause dramatic shifts in efficacy and tropism, allowing the targeting of organs such as the pancreas and brain. Together, these data advance our understanding of lipid nanoparticle chemistry and are expected to contribute to the successful formulation of next-generation mRNA therapies.
