Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver
Open accessAbstract
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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Endosomal escape can be increased by optimizing the pKa values of ionizable lipids.
“Endosomal escape can be increased by optimizing the pKa values of ionizable lipids66,76–78,88,100,140.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [100]
The delivery efficacy of mRNA could be improved by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle-mRNA formulations.
“Moreover, the delivery efficacy of mRNA could be improved, for example, by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [100]
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- Authors
- Miao, L., Lin, J., Huang, Y., Li, L., Delcassian, D., Ge, Y., Shi, Y., & Anderson, D. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Karolinska Institutet (SE)
- Boston Children's Hospital (US)
- Harvard University (US)
- Corresponding author
- Anderson, Daniel G.
- ORCID
- Venue
- Nature Communications
- Published
- 2020-05-15
- Volume
- 11
- Issue
- 1
- Pages
- 2424-2424
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7229004
- OpenAlex
- W3024523552
- Cited by
- 343
- References
- 51
- Citations by year
- 2026: 39 · 2025: 76 · 2024: 77 · 2023: 60 · 2022: 52 · 2021: 31 · 2020: 8
- FWCI
- 12.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Juvenile Diabetes Research Foundation (17-2007-1063, 3-PDF-2015-91-A-N)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- mRNA delivery, liver targeting, albumin receptor, biodegradable lipids, macropinocytosis, endocytosis, membrane fusion, mRNA release
- MeSH terms
- Alkynes, Amines, Animals, Apolipoproteins E, Biocompatible Materials, Erythrocytes, Erythropoietin, Esters, Humans, Lipids, Liver, Male, Mice, Inbred C57BL, Endosomes, RNA, Messenger, Drug Delivery Systems, Receptors, Albumin, Hepatocytes, RNA, Small Interfering, Mice, Nanoparticles, Molecular Dynamics Simulation
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