2. Academic Validation
  3. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver

Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver

  • Nat Commun. 2020 May 15;11(1):2424. doi: 10.1038/s41467-020-16248-y.
Lei Miao # 1,  Jiaqi Lin # 1,  Yuxuan Huang 1,  Linxian Li 1 2,  Derfogail Delcassian 1 3 4,  Yifan Ge 5 6,  Yunhua Shi 1,  Daniel G Anderson 7 8 9 10 11
Affiliations

Affiliations

  • 1 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
  • 2 Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong, China.
  • 3 Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.
  • 4 Division of Regenerative Medicine and Cellular Therapy, University of Nottingham, Nottingham, NG7 2RD, UK.
  • 5 Department of Molecular Biology, Massachusetts General Hospital, Cambridge, MA, 02114, USA.
  • 6 Department of Genetics, Harvard Medical School, Cambridge, MA, 02115, USA.
  • 7 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA. dgander@mit.edu.
  • 8 Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA. dgander@mit.edu.
  • 9 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA. dgander@mit.edu.
  • 10 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. dgander@mit.edu.
  • 11 Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. dgander@mit.edu.
  • # Contributed equally.
PMID: 32415122 DOI: 10.1038/s41467-020-16248-y
Abstract

Lipid-like nanoparticles (LNPs) have potential as non-viral delivery systems for mRNA therapies. However, repeated administrations of LNPs may lead to accumulation of delivery Materials and associated toxicity. To address this challenge, we have developed biodegradable lipids which improve LNPs clearance and reduce toxicity. We modify the backbone structure of Dlin-MC3-DMA by introducing alkyne and ester groups into the lipid tails. We evaluate the performance of these lipids when co-formulated with Other amine containing lipid-like Materials. We demonstrate that these formulations synergistically facilitate robust mRNA delivery with improved tolerability after single and repeated administrations. We further identify albumin-associated macropinocytosis and endocytosis as an ApoE-independent LNP cellular uptake pathway in the liver. Separately, the inclusion of alkyne lipids significantly increases membrane fusion to enhance mRNA release, leading to synergistic improvement of mRNA delivery. We believe that the rational design of LNPs with multiple amine-lipids increases the material space for mRNA delivery.

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