2. Academic Validation
  3. Combinatorial development of nebulized mRNA delivery formulations for the lungs

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

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. dgander@mit.edu.
  • 9 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
  • 10 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
  • 11 Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA. dgander@mit.edu.
  • 12 Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
  • 13 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
  • # 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-159860
    可电离的阳离子氨基脂质
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