Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver
© 2020, The Author(s). 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...
| Main Authors: | , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/133439 |
| _version_ | 1826213684134805504 |
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| author | Miao, Lei Lin, Jiaqi Huang, Yuxuan Li, Linxian Delcassian, Derfogail Ge, Yifan Shi, Yunhua Anderson, Daniel G |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Miao, Lei Lin, Jiaqi Huang, Yuxuan Li, Linxian Delcassian, Derfogail Ge, Yifan Shi, Yunhua Anderson, Daniel G |
| author_sort | Miao, Lei |
| collection | MIT |
| description | © 2020, The Author(s). 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. |
| first_indexed | 2024-09-23T15:53:11Z |
| format | Article |
| id | mit-1721.1/133439 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:53:11Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1334392024-03-19T17:43:49Z Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver Miao, Lei Lin, Jiaqi Huang, Yuxuan Li, Linxian Delcassian, Derfogail Ge, Yifan Shi, Yunhua Anderson, Daniel G Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Institute for Medical Engineering & Science Harvard University--MIT Division of Health Sciences and Technology © 2020, The Author(s). 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. 2021-10-27T19:52:51Z 2021-10-27T19:52:51Z 2020 2021-06-04T16:07:12Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133439 en 10.1038/S41467-020-16248-Y Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Miao, Lei Lin, Jiaqi Huang, Yuxuan Li, Linxian Delcassian, Derfogail Ge, Yifan Shi, Yunhua Anderson, Daniel G Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver |
| title | Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver |
| title_full | Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver |
| title_fullStr | Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver |
| title_full_unstemmed | Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver |
| title_short | Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver |
| title_sort | synergistic lipid compositions for albumin receptor mediated delivery of mrna to the liver |
| url | https://hdl.handle.net/1721.1/133439 |
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