Combinatorial development of nebulized mRNA delivery formulations for the lungs.
Nat Nanotechnol
; 19(3): 364-375, 2024 Mar.
Article
em En
| MEDLINE
| ID: mdl-37985700
ABSTRACT
Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air-liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant improvement in lung mRNA delivery over current state-of-the-art LNPs and polymeric nanoparticles.
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1
Base de dados:
MEDLINE
Assunto principal:
Excipientes
/
Nanopartículas
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article