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 biodegradable, ionizable lipid-like materials called ‘lipidoids’ that readily formulate into nanoparticles containing RNA. Lipidoids efficiently manipulate gene expression in a variety of biological systems, including hepatocytes, white blood cells and tumors. This talk will focus on the cell-free prediction of lipidoid efficacy in delivering mRNA to mice. Furthermore, I will describe a new formulation strategy for the synergistic co-delivery of mRNA and siRNA. Together, these data demonstrate the potential of lipidoid materials to robustly manipulate gene expression in vivo.