2. Academic Validation
  3. In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors

In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors

  • Nat Commun. 2024 Feb 26;15(1):1762. doi: 10.1038/s41467-024-45537-z.
Xuexiang Han # 1 2,  Junchao Xu # 1,  Ying Xu 3,  Mohamad-Gabriel Alameh 4 5,  Lulu Xue 1,  Ningqiang Gong 1,  Rakan El-Mayta 4,  Rohan Palanki 1,  Claude C Warzecha 6,  Gan Zhao 7,  Andrew E Vaughan 7,  James M Wilson 6,  Drew Weissman 4 5,  Michael J Mitchell 8 9 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, 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, 320 Yue Yang Road, Shanghai, 200031, China.
  • 3 Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 4 Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 5 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 6 Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 7 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 8 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 9 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 10 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 11 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 12 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • 13 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. mjmitch@seas.upenn.edu.
  • # Contributed equally.
PMID: 38409275 DOI: 10.1038/s41467-024-45537-z
Abstract

The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human Fibroblast Growth Factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.

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