(21e) Design, Synthesis, and Biological Evaluation of Novel Lipid Nanoparticle Materials for the In Vivo Delivery of Messenger RNA

The delivery of messenger RNA (mRNA) cargoes entrapped in lipid nanoparticles (LNPs) represents one potential strategy to replace deficient or non-existent proteins within target cell populations in vivo. Recent efforts have demonstrated that systemic administration of mRNA LNPs can induce functional protein expression in specific tissues in the body, but lead materials remain limited by their efficacy, biodistribution, and toxicity. Here, we employ rational design principles and synthesize novel LNP materials that can either i. induce higher levels of protein expression at a given dose or ii. modify the site of protein induction. Additionally, we establish critical structure-function parameters within our new mRNA LNP materials, demonstrating that cis alkenes play a pivotal role in improving the efficacy of both degradable and non-degradable mRNA LNP materials. In vivo experiments demonstrate batch-to-batch consistency, dose-response curves, and time course data for our lead mRNA LNPs. Toxicity studies also demonstrate that these materials are well tolerated in vivo. In sum, these studies not only establish highly potent materials for mRNA delivery, but also highlight the importance of employing rational synthetic design principles to better understand and improve our ability to deliver nucleic acids in vivo.