2. Academic Validation
  3. Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo

Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo

  • Nat Chem. 2024 Jul 9. doi: 10.1038/s41557-024-01557-2.
Xuexiang Han # 1 2,  Mohamad-Gabriel Alameh # 3 4 5,  Ningqiang Gong # 1,  Lulu Xue # 1,  Majed Ghattas 3,  Goutham Bojja 3,  Junchao Xu 1,  Gan Zhao 6,  Claude C Warzecha 7,  Marshall S Padilla 1,  Rakan El-Mayta 1 3,  Garima Dwivedi 3,  Ying Xu 8,  Andrew E Vaughan 6,  James M Wilson 7,  Drew Weissman 9 10,  Michael J Mitchell 11 12 13 14 15 16 17 18
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Department of Bioengineering, George Mason University, Fairfax, VA, USA.
  • 6 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8 Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA.
  • 9 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dreww@upenn.edu.
  • 10 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dreww@upenn.edu.
  • 11 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 12 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 13 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 14 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 15 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 16 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 17 Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 18 Center for Precision Engineering for Health, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • # Contributed equally.
PMID: 38982196 DOI: 10.1038/s41557-024-01557-2
Abstract

Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with Cationic Lipids greatly affecting biodistribution, cellular uptake, endosomal escape and transfection efficiency. However, the laborious synthesis of Cationic Lipids limits the discovery of efficacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1 h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identification of a tail-like amine-ring-alkyl aniline that generally affords efficacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen.

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