Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs

• Type of Material: Article
• Authors: Melissa P Lokugamage, Georgia Institute of Technology; Daryll Vanover, Georgia Institute of Technology; Jared Beyersdorf, Georgia Institute of Technology; Marine ZC Hatit, Georgia Institute of Technology; Lauren Rotolo, Georgia Institute of Technology; Elisa Schrader Echeverri, Georgia Institute of Technology; Hannah E Peck, Georgia Institute of Technology; Huanzhen Ni, Georgia Institute of Technology; Jeong-Kee Yoon, Georgia Institute of Technology; YongTae Kim, Georgia Institute of Technology; Philip Santangelo, Emory University; James Dahlman, Emory University
• Language: English
• Date: 2021-09-01
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41551-021-00786-x
• Title of Journal or Parent Work: NATURE BIOMEDICAL ENGINEERING
• Volume: 5
• Issue: 9
• Start Page: 1059
• End Page: 1068
• Keywords: VACCINES; AEROSOL DELIVERY; SIRNA; Technology; IN-VIVO; GENE-THERAPY; FORMULATIONS; Engineering, Biomedical; Engineering; POTENT; Science & Technology

Abstract

Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and structure of LNPs made of lipids, neutral or cationic helper lipids and poly(ethylene glycol) (PEG) by evaluating the performance of LNPs belonging to six clusters occupying extremes in chemical space, and then pooling the lead clusters and expanding their diversity. We found that a low (high) molar ratio of PEG improves the performance of LNPs with neutral (cationic) helper lipids, an identified and optimal LNP for low-dose messenger RNA delivery. Nebulized delivery of an mRNA encoding a broadly neutralizing antibody targeting haemagglutinin via the optimized LNP protected mice from a lethal challenge of the H1N1 subtype of influenza A virus, and delivered mRNA more efficiently than LNPs previously optimized for systemic delivery. A cluster approach to LNP design may facilitate the optimization of LNPs for other administration routes and therapeutics.