Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs
Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and s...
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| Veröffentlicht in: | Nature biomedical engineering 2021-09, Vol.5 (9), p.1059-1068 |
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| creator | Lokugamage, Melissa P. Vanover, Daryll Beyersdorf, Jared Hatit, Marine Z. C. Rotolo, Laura Echeverri, Elisa Schrader Peck, Hannah E. Ni, Huanzhen Yoon, Jeong-Kee Kim, YongTae Santangelo, Philip J. Dahlman, James E. |
| description | Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and structure of LNPs made of lipids, neutral or cationic helper lipids and poly(ethylene glycol) (PEG) by evaluating the performance of LNPs belonging to six clusters occupying extremes in chemical space, and then pooling the lead clusters and expanding their diversity. We found that a low (high) molar ratio of PEG improves the performance of LNPs with neutral (cationic) helper lipids, an identified and optimal LNP for low-dose messenger RNA delivery. Nebulized delivery of an mRNA encoding a broadly neutralizing antibody targeting haemagglutinin via the optimized LNP protected mice from a lethal challenge of the H1N1 subtype of influenza A virus, and delivered mRNA more efficiently than LNPs previously optimized for systemic delivery. A cluster approach to LNP design may facilitate the optimization of LNPs for other administration routes and therapeutics.
Lipid nanoparticles can be optimized for the efficient delivery of therapeutic mRNAs to the lung via nebulization, as shown for the delivery of a therapeutic antibody in mice challenged with a lethal dose of the H1N1 influenza A virus. |
| doi_str_mv | 10.1038/s41551-021-00786-x |
| format | Article |
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Lipid nanoparticles can be optimized for the efficient delivery of therapeutic mRNAs to the lung via nebulization, as shown for the delivery of a therapeutic antibody in mice challenged with a lethal dose of the H1N1 influenza A virus.</description><identifier>ISSN: 2157-846X</identifier><identifier>EISSN: 2157-846X</identifier><identifier>DOI: 10.1038/s41551-021-00786-x</identifier><identifier>PMID: 34616046</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/62 ; 42/47 ; 45/47 ; 45/77 ; 639/166/898 ; 639/166/985 ; 64/60 ; Animals ; Antibodies ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; Cations ; Chemical compounds ; Clusters ; Design optimization ; Drug delivery ; Drug development ; Hemagglutinins ; Influenza ; Influenza A ; Influenza A Virus, H1N1 Subtype ; Lethal dose ; Lipids ; Liposomes ; Lung ; Lungs ; Mice ; mRNA ; Nanoparticles ; Performance enhancement ; Performance evaluation ; Pharmaceuticals ; Polyethylene glycol ; RNA, Messenger ; RNA, Small Interfering ; Swine flu ; Viruses</subject><ispartof>Nature biomedical engineering, 2021-09, Vol.5 (9), p.1059-1068</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>Copyright Nature Publishing Group Sep 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c485t-5fcc4fe48eb02d2ff3a291cfac8532ea36149b5176e71aacb67b85e0d64088433</citedby><cites>FETCH-LOGICAL-c485t-5fcc4fe48eb02d2ff3a291cfac8532ea36149b5176e71aacb67b85e0d64088433</cites><orcidid>0000-0001-7352-0339 ; 0000-0002-8835-8247 ; 0000-0001-7580-436X ; 0000-0002-5713-6596</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41551-021-00786-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41551-021-00786-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34616046$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lokugamage, Melissa P.</creatorcontrib><creatorcontrib>Vanover, Daryll</creatorcontrib><creatorcontrib>Beyersdorf, Jared</creatorcontrib><creatorcontrib>Hatit, Marine Z. C.</creatorcontrib><creatorcontrib>Rotolo, Laura</creatorcontrib><creatorcontrib>Echeverri, Elisa Schrader</creatorcontrib><creatorcontrib>Peck, Hannah E.</creatorcontrib><creatorcontrib>Ni, Huanzhen</creatorcontrib><creatorcontrib>Yoon, Jeong-Kee</creatorcontrib><creatorcontrib>Kim, YongTae</creatorcontrib><creatorcontrib>Santangelo, Philip J.</creatorcontrib><creatorcontrib>Dahlman, James E.</creatorcontrib><title>Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs</title><title>Nature biomedical engineering</title><addtitle>Nat Biomed Eng</addtitle><addtitle>Nat Biomed Eng</addtitle><description>Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and structure of LNPs made of lipids, neutral or cationic helper lipids and poly(ethylene glycol) (PEG) by evaluating the performance of LNPs belonging to six clusters occupying extremes in chemical space, and then pooling the lead clusters and expanding their diversity. We found that a low (high) molar ratio of PEG improves the performance of LNPs with neutral (cationic) helper lipids, an identified and optimal LNP for low-dose messenger RNA delivery. Nebulized delivery of an mRNA encoding a broadly neutralizing antibody targeting haemagglutinin via the optimized LNP protected mice from a lethal challenge of the H1N1 subtype of influenza A virus, and delivered mRNA more efficiently than LNPs previously optimized for systemic delivery. A cluster approach to LNP design may facilitate the optimization of LNPs for other administration routes and therapeutics.
Lipid nanoparticles can be optimized for the efficient delivery of therapeutic mRNAs to the lung via nebulization, as shown for the delivery of a therapeutic antibody in mice challenged with a lethal dose of the H1N1 influenza A virus.</description><subject>101/62</subject><subject>42/47</subject><subject>45/47</subject><subject>45/77</subject><subject>639/166/898</subject><subject>639/166/985</subject><subject>64/60</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>Cations</subject><subject>Chemical compounds</subject><subject>Clusters</subject><subject>Design optimization</subject><subject>Drug delivery</subject><subject>Drug development</subject><subject>Hemagglutinins</subject><subject>Influenza</subject><subject>Influenza A</subject><subject>Influenza A Virus, H1N1 Subtype</subject><subject>Lethal dose</subject><subject>Lipids</subject><subject>Liposomes</subject><subject>Lung</subject><subject>Lungs</subject><subject>Mice</subject><subject>mRNA</subject><subject>Nanoparticles</subject><subject>Performance enhancement</subject><subject>Performance evaluation</subject><subject>Pharmaceuticals</subject><subject>Polyethylene glycol</subject><subject>RNA, Messenger</subject><subject>RNA, Small Interfering</subject><subject>Swine flu</subject><subject>Viruses</subject><issn>2157-846X</issn><issn>2157-846X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kUtL7jAQhoMoKuofcHEouHFTzb3pUuR4AVEQBXchTScaaZuatKL-evP5qUfOwkWYwDzzJMyL0C7BBwQzdZg4EYKUmOaDKyXLlxW0SYmoSsXl3eqP-wbaSekRY0xqxutKrKMNxiWRmMtNpK_Gyff-zUw-DEVwRedH3xaDGcJo4uRtB6lwIRbTAxQtdP4Z4uuCG6CZO_8G7aITzQhzhov--vKomMIH3c3DfdpGa850CXY-6xa6Pfl7c3xWXlydnh8fXZSWKzGVwlnLHXAFDaYtdY4ZWhPrjFWCUTBMEl43glQSKmKMbWTVKAG4lRwrxRnbQvtL7xjD0wxp0r1PFrrODBDmpKlQGFOJlczo3n_oY5jjkH-XqarmWYkXQrqkbAwpRXB6jL438VUTrBcJ6GUCOiegPxLQL3noz6d6bnpov0e-9p0BtgRSbg33EP-9_Yv2HSjKkhw</recordid><startdate>20210901</startdate><enddate>20210901</enddate><creator>Lokugamage, Melissa P.</creator><creator>Vanover, Daryll</creator><creator>Beyersdorf, Jared</creator><creator>Hatit, Marine Z. 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C.</au><au>Rotolo, Laura</au><au>Echeverri, Elisa Schrader</au><au>Peck, Hannah E.</au><au>Ni, Huanzhen</au><au>Yoon, Jeong-Kee</au><au>Kim, YongTae</au><au>Santangelo, Philip J.</au><au>Dahlman, James E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs</atitle><jtitle>Nature biomedical engineering</jtitle><stitle>Nat Biomed Eng</stitle><addtitle>Nat Biomed Eng</addtitle><date>2021-09-01</date><risdate>2021</risdate><volume>5</volume><issue>9</issue><spage>1059</spage><epage>1068</epage><pages>1059-1068</pages><issn>2157-846X</issn><eissn>2157-846X</eissn><abstract>Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and structure of LNPs made of lipids, neutral or cationic helper lipids and poly(ethylene glycol) (PEG) by evaluating the performance of LNPs belonging to six clusters occupying extremes in chemical space, and then pooling the lead clusters and expanding their diversity. We found that a low (high) molar ratio of PEG improves the performance of LNPs with neutral (cationic) helper lipids, an identified and optimal LNP for low-dose messenger RNA delivery. Nebulized delivery of an mRNA encoding a broadly neutralizing antibody targeting haemagglutinin via the optimized LNP protected mice from a lethal challenge of the H1N1 subtype of influenza A virus, and delivered mRNA more efficiently than LNPs previously optimized for systemic delivery. A cluster approach to LNP design may facilitate the optimization of LNPs for other administration routes and therapeutics.
Lipid nanoparticles can be optimized for the efficient delivery of therapeutic mRNAs to the lung via nebulization, as shown for the delivery of a therapeutic antibody in mice challenged with a lethal dose of the H1N1 influenza A virus.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34616046</pmid><doi>10.1038/s41551-021-00786-x</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-7352-0339</orcidid><orcidid>https://orcid.org/0000-0002-8835-8247</orcidid><orcidid>https://orcid.org/0000-0001-7580-436X</orcidid><orcidid>https://orcid.org/0000-0002-5713-6596</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 101/62 42/47 45/47 45/77 639/166/898 639/166/985 64/60 Animals Antibodies Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Cations Chemical compounds Clusters Design optimization Drug delivery Drug development Hemagglutinins Influenza Influenza A Influenza A Virus, H1N1 Subtype Lethal dose Lipids Liposomes Lung Lungs Mice mRNA Nanoparticles Performance enhancement Performance evaluation Pharmaceuticals Polyethylene glycol RNA, Messenger RNA, Small Interfering Swine flu Viruses |
| title | Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs |
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