Lipid nanoparticle screening in nonhuman primates with minimal loss of life

Few lipid nanoparticle (LNP)-mRNA drug candidates are tested in nonhuman primates (NHPs), in part because the experiments require more animals than is considered ethical. Understanding the extent to which delivery in mice predicts delivery in NHPs could make LNP discovery more efficient. We create a pool of sterile barcoded LNPs that were frozen, aliquoted, then administered when an end of life (EoL) NHP became available. We then administer this pool of 45 LNP-aVHH mRNAs with different chemistries intravenously to mice, EoL NHPs with gastrointestinal inflammation, and control NHPs. A higher amount of aVHH expression is seen in NHPs than in mice, indicating higher functional delivery. We characterize systemic physiological responses to LNP treatment using 47 clinically relevant variables, and analyze the transcriptomic response alongside delivery in single cells from three tissues in vivo. These data suggest that multiple lipoprotein receptors may be associated with delivery to non-liver tissues. Altogether, EoL NHPs reduce animal use and may be informative preclinical models.