Combinatorial development of nebulized mRNA delivery formulations for the lungs.

Autor: Jiang AY; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA., Witten J; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Raji IO; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA., Eweje F; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.; Harvard/MIT MD-PhD Program, Boston, MA, USA., MacIsaac C; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA., Meng S; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Oladimeji FA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Hu Y; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA., Manan RS; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA., Langer R; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA.; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA., Anderson DG; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.; Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA. dgander@mit.edu.; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
Jazyk: angličtina
Zdroj: Nature nanotechnology [Nat Nanotechnol] 2024 Mar; Vol. 19 (3), pp. 364-375. Date of Electronic Publication: 2023 Nov 20.
DOI: 10.1038/s41565-023-01548-3
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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