Non-liver mRNA Delivery.

ConspectusmRNA drugs can preempt infectious disease and treat Mendelian disorders, such as sickle cell anemia, muscular dystrophy, and cystic fibrosis, as well as autoimmunity and cancer. The three major therapeutic areas for which mRNA delivery is currently being explored are antigen production, including the COVID-19 vaccine, protein replacement therapy, and genome engineering. It was demonstrated 30 years ago that introducing in vitro transcribed mRNA intramuscularly results in detectable protein expression for specific antigens protecting against the likes of influenza and cancer. Utilizing mRNA as a therapeutic modality, however, is challenging. mRNA is large and anionic and, as a result, cannot passively diffuse across the negatively charged plasma membrane. In addition, RNases present in the bloodstream and tissues rapidly degrade mRNA, and its administration induces the innate immune response. In consequence, lipid-, polymer-, dendrimer-, and natural membrane-based mRNA drug delivery systems have been developed to deliver mRNA to target cells. Significant efforts and investments have been made to translate some of these systems into the clinic. Specifically, systemically administered lipid nanoparticles (LNPs) have delivered mRNA to the liver, and intramuscularly administered LNPs have delivered mRNA to immune cells to protect against coronavirus disease of 2019. However, clinically relevant delivery in non-liver tissues such as the spleen, lungs, heart, eye, central nervous system, and lymphatics requires improved drug delivery systems.In this Account, we provide an overview of key advances that have led us to Food and Drug Administration approval for the Pfizer/BioNTech mRNA-based vaccine against SARS-CoV-2 and Emergency Use Authorization for the Moderna mRNA-based vaccine against the same disease, and we explain how these developments will contribute to the clinical translation of mRNA therapeutics targeted outside of the liver. We first focus on the chemical modifications and sequence optimization that can improve the potency of mRNA, resulting in greatly improved pharmacokinetics. After detailing what makes an ideal mRNA payload, we review drug delivery systems used to deliver the payload into target cells. We describe efforts to reduce clearance by the liver, a key obstacle to the development of non-liver therapies. We then consider recent examples of nanoparticles that have delivered mRNA to non-liver tissues. Finally, we discuss current clinical mRNA programs, focusing on the COVID vaccines and highlighting lessons that may be applied to future mRNA drugs.