Combinatorial development of nebulized mRNA delivery formulations for the lungs

  • Nat Nanotechnol. 2024 Mar;19(3):364-375. doi: 10.1038/s41565-023-01548-3.
Allen Y Jiang  #  1  2 ,  Jacob Witten  #  1  2  3 ,  Idris O Raji  #  1  2  4 ,  Feyisayo Eweje  5  6 ,  Corina MacIsaac  2  5 ,  Sabrina Meng  3 ,  Favour A Oladimeji  3 ,  Yizong Hu  2 ,  Rajith S Manan  1  2 ,  Robert Langer  1  2  3  4  5  7 ,  Daniel G Anderson  8  9  10  11  12  13
Affiliations
  • 1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 2. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 4. Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA.
  • 5. Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 6. Harvard/MIT MD-PhD Program, Boston, MA, USA.
  • 7. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 8. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
  • 9. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
  • 10. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
  • 11. Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA. [email protected].
  • 12. Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
  • 13. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
  • # Contributed equally.
PMID: 37985700 DOI: 10.1038/s41565-023-01548-3
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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