Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes
Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synth...
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| Veröffentlicht in: | Journal of the American Chemical Society 2021-12, Vol.143 (50), p.21321-21330 |
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| container_title | Journal of the American Chemical Society |
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| creator | Liu, Shuai Wang, Xu Yu, Xueliang Cheng, Qiang Johnson, Lindsay T Chatterjee, Sumanta Zhang, Di Lee, Sang M Sun, Yehui Lin, Ting-Chih Liu, John L Siegwart, Daniel J |
| description | Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. This zwitterionic phospholipidation methodology provides a versatile and generalizable postmodification strategy to introduce zwitterions into the side chains of cationic polymers, extending the utility of cationic polymer families for precise mRNA delivery and demonstrating substantial potential for immunotherapeutic applications. |
| doi_str_mv | 10.1021/jacs.1c09822 |
| format | Article |
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Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. This zwitterionic phospholipidation methodology provides a versatile and generalizable postmodification strategy to introduce zwitterions into the side chains of cationic polymers, extending the utility of cationic polymer families for precise mRNA delivery and demonstrating substantial potential for immunotherapeutic applications.</description><identifier>ISSN: 0002-7863</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/jacs.1c09822</identifier><identifier>PMID: 34878786</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cations - chemistry ; Endosomes - metabolism ; Gene Transfer Techniques ; Lymph Nodes - metabolism ; Mice ; Mice, Inbred C57BL ; Phospholipids - chemistry ; Polymers - chemistry ; RNA, Messenger - chemistry ; RNA, Messenger - metabolism ; Spleen - metabolism</subject><ispartof>Journal of the American Chemical Society, 2021-12, Vol.143 (50), p.21321-21330</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a483t-66073d5540a7585c759fcdb294b34ba2cd99ac2ab21b499742b1f872716725a73</citedby><cites>FETCH-LOGICAL-a483t-66073d5540a7585c759fcdb294b34ba2cd99ac2ab21b499742b1f872716725a73</cites><orcidid>0000-0002-8405-6743 ; 0000-0003-3823-1931 ; 0000-0003-0215-6095 ; 0000-0002-5213-5084 ; 0000-0002-4563-5486</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jacs.1c09822$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jacs.1c09822$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34878786$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Shuai</creatorcontrib><creatorcontrib>Wang, Xu</creatorcontrib><creatorcontrib>Yu, Xueliang</creatorcontrib><creatorcontrib>Cheng, Qiang</creatorcontrib><creatorcontrib>Johnson, Lindsay T</creatorcontrib><creatorcontrib>Chatterjee, Sumanta</creatorcontrib><creatorcontrib>Zhang, Di</creatorcontrib><creatorcontrib>Lee, Sang M</creatorcontrib><creatorcontrib>Sun, Yehui</creatorcontrib><creatorcontrib>Lin, Ting-Chih</creatorcontrib><creatorcontrib>Liu, John L</creatorcontrib><creatorcontrib>Siegwart, Daniel J</creatorcontrib><title>Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes</title><title>Journal of the American Chemical Society</title><addtitle>J. Am. Chem. Soc</addtitle><description>Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. This zwitterionic phospholipidation methodology provides a versatile and generalizable postmodification strategy to introduce zwitterions into the side chains of cationic polymers, extending the utility of cationic polymer families for precise mRNA delivery and demonstrating substantial potential for immunotherapeutic applications.</description><subject>Animals</subject><subject>Cations - chemistry</subject><subject>Endosomes - metabolism</subject><subject>Gene Transfer Techniques</subject><subject>Lymph Nodes - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Phospholipids - chemistry</subject><subject>Polymers - chemistry</subject><subject>RNA, Messenger - chemistry</subject><subject>RNA, Messenger - metabolism</subject><subject>Spleen - metabolism</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptUcFu1DAQtRCILoUbZ-QjB1LsiR3HF6RqoVBpVRCFCxfLcRzWKydObW9R_p6k3ZYiVT6MZ96bN6N5CL2m5IQSoO932qQTaoisAZ6gFeVACk6heopWhBAoRF2VR-hFSrs5ZVDT5-ioZLWYX7VC468_LmcbXRicwd-2IY3b4N3oWp3nGg4dXt_8FjT4qbcx4TNtnHdZZ5vw5ZSy7We0_35xij9a765tnHAO-HL01g5YDy3eTP24xRehtekletZpn-yrQzxGP88-_Vh_KTZfP5-vTzeFZnWZi6oiomw5Z0QLXnMjuOxM24BkTckaDaaVUhvQDdCGSSkYNLSrBQhaCeBalMfow63uuG962xo75Ki9GqPrdZxU0E79jwxuq36HayVZKSQsAm8PAjFc7W3KqnfJWO_1YMM-KahIzTiIG-q7W6qJIaVou_sxlKjFJLWYpA4mzfQ3D1e7J9-58m_00rUL-zjMl3pc6y_35Jz0</recordid><startdate>20211222</startdate><enddate>20211222</enddate><creator>Liu, Shuai</creator><creator>Wang, Xu</creator><creator>Yu, Xueliang</creator><creator>Cheng, Qiang</creator><creator>Johnson, Lindsay T</creator><creator>Chatterjee, Sumanta</creator><creator>Zhang, Di</creator><creator>Lee, Sang M</creator><creator>Sun, Yehui</creator><creator>Lin, Ting-Chih</creator><creator>Liu, John L</creator><creator>Siegwart, Daniel J</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8405-6743</orcidid><orcidid>https://orcid.org/0000-0003-3823-1931</orcidid><orcidid>https://orcid.org/0000-0003-0215-6095</orcidid><orcidid>https://orcid.org/0000-0002-5213-5084</orcidid><orcidid>https://orcid.org/0000-0002-4563-5486</orcidid></search><sort><creationdate>20211222</creationdate><title>Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes</title><author>Liu, Shuai ; Wang, Xu ; Yu, Xueliang ; Cheng, Qiang ; Johnson, Lindsay T ; Chatterjee, Sumanta ; Zhang, Di ; Lee, Sang M ; Sun, Yehui ; Lin, Ting-Chih ; Liu, John L ; Siegwart, Daniel J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a483t-66073d5540a7585c759fcdb294b34ba2cd99ac2ab21b499742b1f872716725a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Cations - chemistry</topic><topic>Endosomes - metabolism</topic><topic>Gene Transfer Techniques</topic><topic>Lymph Nodes - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Phospholipids - chemistry</topic><topic>Polymers - chemistry</topic><topic>RNA, Messenger - chemistry</topic><topic>RNA, Messenger - metabolism</topic><topic>Spleen - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Shuai</creatorcontrib><creatorcontrib>Wang, Xu</creatorcontrib><creatorcontrib>Yu, Xueliang</creatorcontrib><creatorcontrib>Cheng, Qiang</creatorcontrib><creatorcontrib>Johnson, Lindsay T</creatorcontrib><creatorcontrib>Chatterjee, Sumanta</creatorcontrib><creatorcontrib>Zhang, Di</creatorcontrib><creatorcontrib>Lee, Sang M</creatorcontrib><creatorcontrib>Sun, Yehui</creatorcontrib><creatorcontrib>Lin, Ting-Chih</creatorcontrib><creatorcontrib>Liu, John L</creatorcontrib><creatorcontrib>Siegwart, Daniel J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American Chemical Society</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Shuai</au><au>Wang, Xu</au><au>Yu, Xueliang</au><au>Cheng, Qiang</au><au>Johnson, Lindsay T</au><au>Chatterjee, Sumanta</au><au>Zhang, Di</au><au>Lee, Sang M</au><au>Sun, Yehui</au><au>Lin, Ting-Chih</au><au>Liu, John L</au><au>Siegwart, Daniel J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes</atitle><jtitle>Journal of the American Chemical Society</jtitle><addtitle>J. Am. Chem. Soc</addtitle><date>2021-12-22</date><risdate>2021</risdate><volume>143</volume><issue>50</issue><spage>21321</spage><epage>21330</epage><pages>21321-21330</pages><issn>0002-7863</issn><eissn>1520-5126</eissn><abstract>Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. 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| subjects | Animals Cations - chemistry Endosomes - metabolism Gene Transfer Techniques Lymph Nodes - metabolism Mice Mice, Inbred C57BL Phospholipids - chemistry Polymers - chemistry RNA, Messenger - chemistry RNA, Messenger - metabolism Spleen - metabolism |
| title | Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes |
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