(497a) Branched-Tail Lipid Nanoparticles Potently Deliver mRNA across Multiple Murine Models

Messenger RNA (mRNA) has the potential to revolutionize modern medicine. We have already seen the beginning of this with the mRNA based COVID-19 vaccines by Moderna and Pfizer/BioNTech. Therapeutic mRNA can be used for protein replacement therapies, immunotherapies, gene editing, and many other applications. To deliver the fragile mRNA cargo to its target, a delivery vehicle is needed. Lipid nanoparticles are the most clinically advanced mRNA delivery vehicle. The preclinical screening of mRNA lipid nanoparticles is critical for their advancement from benchtop to bedside. Most preclinical studies use C57BL/6 and BALB/c mice, which are genetically identical (inbred). These mice are often selected as they tend to reduce within-group variance. Resulting in lowering the number of animals needed. However, outbred mice have been shown to more accurately mimic the genetic diversity of humans, and some strains (e.g. CD-1) are more cost-effective than inbred mice. To-date a direct comparison of mRNA lipid nanoparticles efficacy in inbred and outbred murine models has not been done. This study aims to investigate the effect that chemistry has on delivery efficacy and immunogenicity in inbred and outbred murine models. We have designed 20 novel branch-tail lipid nanoparticles to screen in C57BL/6, BALB/c, and CD-1 mice. Our work provides a direct comparison of mRNA lipid nanoparticle efficacy in inbred and outbred mouse strains for the first time. Of the 20 novel lipid nanoparticles screened we have identified nine promising candidates for potent mRNA delivery. Additionally, we also screened lipid nanoparticles in outbred Sprague Dawley rats. Furthermore, we will investigate the acute immune response observed after delivery of lipid nanoparticles. Future work will evaluate if there are efficacy, specificity, or immunological changes when the route of delivery is altered.