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

Lei Miao, Jiaqi Lin, Yuxuan Huang, Linxian Li, Derfogail Delcassian, Yifan Ge, Yunhua Shi and Daniel G. Anderson ()
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Lei Miao: Massachusetts Institute of Technology
Jiaqi Lin: Massachusetts Institute of Technology
Yuxuan Huang: Massachusetts Institute of Technology
Linxian Li: Massachusetts Institute of Technology
Derfogail Delcassian: Massachusetts Institute of Technology
Yifan Ge: Massachusetts General Hospital
Yunhua Shi: Massachusetts Institute of Technology
Daniel G. Anderson: Massachusetts Institute of Technology

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16248-y

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