In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors
Abstract The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinat...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45537-z |
| _version_ | 1797274028009848832 |
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| author | 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 Weissman Michael J. Mitchell |
| author_facet | 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 Weissman Michael J. Mitchell |
| author_sort | Xuexiang Han |
| collection | DOAJ |
| description | Abstract The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery. |
| first_indexed | 2024-03-07T14:52:31Z |
| format | Article |
| id | doaj.art-5c7c469fc7ef44afbf32232dfd7a12e4 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:31Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5c7c469fc7ef44afbf32232dfd7a12e42024-03-05T19:36:31ZengNature PortfolioNature Communications2041-17232024-02-0115111310.1038/s41467-024-45537-zIn situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editorsXuexiang Han0Junchao Xu1Ying Xu2Mohamad-Gabriel Alameh3Lulu Xue4Ningqiang Gong5Rakan El-Mayta6Rohan Palanki7Claude C. Warzecha8Gan Zhao9Andrew E. Vaughan10James M. Wilson11Drew Weissman12Michael J. Mitchell13Department of Bioengineering, University of PennsylvaniaDepartment of Bioengineering, University of PennsylvaniaDepartment of Chemistry, Case Western Reserve UniversityDepartment of Medicine, University of PennsylvaniaDepartment of Bioengineering, University of PennsylvaniaDepartment of Bioengineering, University of PennsylvaniaDepartment of Medicine, University of PennsylvaniaDepartment of Bioengineering, University of PennsylvaniaGene Therapy Program, Perelman School of Medicine, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of PennsylvaniaGene Therapy Program, Perelman School of Medicine, University of PennsylvaniaDepartment of Medicine, University of PennsylvaniaDepartment of Bioengineering, University of PennsylvaniaAbstract The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.https://doi.org/10.1038/s41467-024-45537-z |
| spellingShingle | 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 Weissman Michael J. Mitchell In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors Nature Communications |
| title | In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors |
| title_full | In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors |
| title_fullStr | In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors |
| title_full_unstemmed | In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors |
| title_short | In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors |
| title_sort | in situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mrna therapeutics and gene editors |
| url | https://doi.org/10.1038/s41467-024-45537-z |
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