Targeted Gastrointestinal Delivery of mRNA Lipid Nanoparticles Enables Systemic Vaccination and Glucagon-like Peptide-1 Metabolic Therapy

Abstract Lipid nanoparticles (LNPs) administered parenterally often show poor localization to multiple tissue types, including the pancreas and gastrointestinal (GI) tract. Furthermore, patients typically prefer orally administered drugs to those that are given parenterally. We therefore investigated whether GI LNP administration to buccal, gastric, small intestinal, colonic, and rectal submucosal tissues could simultaneously circumvent parenteral administration while enhancing LNP delivery to previously inaccessible locations. We found that, in addition to local targeting, gastric LNP administration achieved an order of magnitude greater pancreas delivery in rodents than intravenous administration. Gastric dosing of glucagon-like peptide-1 mRNA also improved blood glucose regulation in mice compared with phosphate-buffered saline controls. Additionally, we found that buccal LNP administration targeted local and lymphatic tissues. Furthermore, dosing mice with ovalbumin mRNA resulted in equivalent immunoglobulin G blood titers to those of intramuscular delivery. These results suggest that GI administration can reprogram LNP biodistribution, expanding therapeutic opportunities for both local and systemic nucleic acid delivery.