TY - JOUR

T1 - Lipid nanoparticles for local delivery of mRNA to the respiratory tract

T2 - Effect of PEG-lipid content and administration route

AU - Ongun, Melike

AU - Lokras, Abhijeet Girish

AU - Baghel, Saahil

AU - Shi, Zhenning

AU - Schmidt, Signe Tandrup

AU - Franzyk, Henrik

AU - Rades, Thomas

AU - Sebastiani, Federica

AU - Thakur, Aneesh

AU - Foged, Camilla

N1 - Copyright © 2024. Published by Elsevier B.V.

PY - 2024

Y1 - 2024

N2 - Design of inhalable mRNA therapeutics is promising, because local administration in the respiratory tract is minimally invasive and induces a local response. However, several challenges related to administration via inhalation and respiratory tract barriers have so far prevented the progress of inhaled mRNA therapeutics. Here, we investigated factors of importance for lipid nanoparticle (LNP)-mediated delivery of mRNA to the respiratory tract. We hypothesized that: (i) the PEG-lipid content is important for providing colloidal stability during aerosolization and for mucosal delivery, (ii) the PEG-lipid contentinfluences mRNA expression in the lungs, and (iii) the route of administration (nasal versus pulmonary) influences mRNA expression in the lungs. In this study, we aimed to optimize the PEG-lipid content for mucosal delivery and to investigatethe effect of administration route on the kinetics of mRNA expression. Our results show that increasing the PEG-lipid content improves the colloidal stability during the aerosolization process, but has a negative impact on the transfection efficiencyin vitro. The kinetics of protein expressionin vivois dependent on the route of administration, and we found that pulmonaryadministration of mRNA-LNPs to mice results inlonger protein expression than nasaladministration. These results demonstrate that the design of the delivery system and the route of administration are importantfor achieving high mRNA transfection efficiency in the respiratory tract.

AB - Design of inhalable mRNA therapeutics is promising, because local administration in the respiratory tract is minimally invasive and induces a local response. However, several challenges related to administration via inhalation and respiratory tract barriers have so far prevented the progress of inhaled mRNA therapeutics. Here, we investigated factors of importance for lipid nanoparticle (LNP)-mediated delivery of mRNA to the respiratory tract. We hypothesized that: (i) the PEG-lipid content is important for providing colloidal stability during aerosolization and for mucosal delivery, (ii) the PEG-lipid contentinfluences mRNA expression in the lungs, and (iii) the route of administration (nasal versus pulmonary) influences mRNA expression in the lungs. In this study, we aimed to optimize the PEG-lipid content for mucosal delivery and to investigatethe effect of administration route on the kinetics of mRNA expression. Our results show that increasing the PEG-lipid content improves the colloidal stability during the aerosolization process, but has a negative impact on the transfection efficiencyin vitro. The kinetics of protein expressionin vivois dependent on the route of administration, and we found that pulmonaryadministration of mRNA-LNPs to mice results inlonger protein expression than nasaladministration. These results demonstrate that the design of the delivery system and the route of administration are importantfor achieving high mRNA transfection efficiency in the respiratory tract.

U2 - 10.1016/j.ejpb.2024.114266

DO - 10.1016/j.ejpb.2024.114266

M3 - Journal article

C2 - 38499255

VL - 198

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

M1 - 114266

ER -