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

Author

Listed:
  • Lei Miao

    (Massachusetts Institute of Technology)

  • Jiaqi Lin

    (Massachusetts Institute of Technology)

  • Yuxuan Huang

    (Massachusetts Institute of Technology)

  • Linxian Li

    (Massachusetts Institute of Technology
    Karolinska Institutet)

  • Derfogail Delcassian

    (Massachusetts Institute of Technology
    Boston Children’s Hospital
    University of Nottingham)

  • Yifan Ge

    (Massachusetts General Hospital
    Harvard Medical School)

  • Yunhua Shi

    (Massachusetts Institute of Technology)

  • Daniel G. Anderson

    (Massachusetts Institute of Technology
    Boston Children’s Hospital
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

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.

Suggested Citation

  • Lei Miao & Jiaqi Lin & Yuxuan Huang & Linxian Li & Derfogail Delcassian & Yifan Ge & Yunhua Shi & Daniel G. Anderson, 2020. "Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16248-y
    DOI: 10.1038/s41467-020-16248-y
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    Cited by:

    1. Man Wu & Pok Man Hau & Linxian Li & Chi Man Tsang & Yike Yang & Aziz Taghbalout & Grace Tin-Yun Chung & Shin Yee Hui & Wing Chung Tang & Nathaniel Jillette & Jacqueline Jufen Zhu & Horace Hok Yeung Le, 2024. "Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Xuexiang Han & Junchao Xu & Ying Xu & Mohamad-Gabriel Alameh & Lulu Xue & Ningqiang Gong & Rakan El-Mayta & Rohan Palanki & Claude C. Warzecha & Gan Zhao & Andrew E. Vaughan & James M. Wilson & Drew W, 2024. "In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Xuexiang Han & Hanwen Zhang & Kamila Butowska & Kelsey L. Swingle & Mohamad-Gabriel Alameh & Drew Weissman & Michael J. Mitchell, 2021. "An ionizable lipid toolbox for RNA delivery," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
    4. Kai Liu & Ralf Nilsson & Elisa Lázaro-Ibáñez & Hanna Duàn & Tasso Miliotis & Marie Strimfors & Michael Lerche & Ana Rita Salgado Ribeiro & Johan Ulander & Daniel Lindén & Anna Salvati & Alan Sabirsh, 2023. "Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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