Lipid nanoparticle‐mediated delivery of IL‐21‐encoding mRNA induces viral clearance in mouse models of hepatitis B virus persistence
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options cannot effectively induce its clearance. Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS)...
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| Veröffentlicht in: | Journal of medical virology 2023-09, Vol.95 (9), p.e29062-e29062 |
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| container_title | Journal of medical virology |
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| creator | Shen, Zhongliang Zhang, Shenyan Jiang, Qirong Liu, Nannan Li, Fahong Gao, Zixiang Pan, Shaokun Hao, Weiju Deng, Qiang Liu, Jing Zhang, Jiming Xie, Youhua |
| description | Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options cannot effectively induce its clearance. Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS) and identified interleukin‐21 (IL‐21) as a potent inducer of HBV clearance. Lipid nanoparticle (LNP) mediated delivery of mRNA has proven to be a highly safe and effective delivery platform. This work explored the applicability and effectiveness of the mRNA‐LNP platform in IL‐21‐based HBV therapies. First, LNP‐encapsulated murine IL‐21 mRNA (LNP‐IL‐21) was prepared, characterized, and demonstrated to engender IL‐21 expression in vitro and in vivo. Next, LNP‐IL‐21 was shown to induce clearance of both serum and intrahepatic HBV antigen and DNA in two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA), respectively, which was associated with HBV‐specific humoral and cellular immune responses. Furthermore, peripheral blood mononuclear cells from BPS persistence mice treated ex vivo with LNP‐IL‐21 and HBV surface antigen (HBsAg) could induce similar HBV clearance upon infusion into recipient mice. These findings indicated that IL‐21 combined with mRNA‐LNP platform represents a valid and promising strategy for developing novel therapeutics against chronic HBV infection. |
| doi_str_mv | 10.1002/jmv.29062 |
| format | Article |
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Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS) and identified interleukin‐21 (IL‐21) as a potent inducer of HBV clearance. Lipid nanoparticle (LNP) mediated delivery of mRNA has proven to be a highly safe and effective delivery platform. This work explored the applicability and effectiveness of the mRNA‐LNP platform in IL‐21‐based HBV therapies. First, LNP‐encapsulated murine IL‐21 mRNA (LNP‐IL‐21) was prepared, characterized, and demonstrated to engender IL‐21 expression in vitro and in vivo. Next, LNP‐IL‐21 was shown to induce clearance of both serum and intrahepatic HBV antigen and DNA in two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA), respectively, which was associated with HBV‐specific humoral and cellular immune responses. Furthermore, peripheral blood mononuclear cells from BPS persistence mice treated ex vivo with LNP‐IL‐21 and HBV surface antigen (HBsAg) could induce similar HBV clearance upon infusion into recipient mice. These findings indicated that IL‐21 combined with mRNA‐LNP platform represents a valid and promising strategy for developing novel therapeutics against chronic HBV infection.</description><identifier>ISSN: 0146-6615</identifier><identifier>EISSN: 1096-9071</identifier><identifier>DOI: 10.1002/jmv.29062</identifier><language>eng</language><publisher>London: Wiley Subscription Services, Inc</publisher><subject>Animal models ; Antigens ; Chronic infection ; Circular DNA ; Hepatitis ; Hepatitis B ; Hepatitis B surface antigen ; Immune clearance ; Immune response (cell-mediated) ; Immune response (humoral) ; Leukocytes (mononuclear) ; Lipids ; Nanoparticles ; Peripheral blood mononuclear cells ; Virology ; Viruses</subject><ispartof>Journal of medical virology, 2023-09, Vol.95 (9), p.e29062-e29062</ispartof><rights>2023 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c325t-ea68e2095d9f705f9b8046c8d52c0ab800db69926d9e185340b66962460eb0913</citedby><cites>FETCH-LOGICAL-c325t-ea68e2095d9f705f9b8046c8d52c0ab800db69926d9e185340b66962460eb0913</cites><orcidid>0000-0002-2466-3736 ; 0000-0001-8566-9149</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids></links><search><creatorcontrib>Shen, Zhongliang</creatorcontrib><creatorcontrib>Zhang, Shenyan</creatorcontrib><creatorcontrib>Jiang, Qirong</creatorcontrib><creatorcontrib>Liu, Nannan</creatorcontrib><creatorcontrib>Li, Fahong</creatorcontrib><creatorcontrib>Gao, Zixiang</creatorcontrib><creatorcontrib>Pan, Shaokun</creatorcontrib><creatorcontrib>Hao, Weiju</creatorcontrib><creatorcontrib>Deng, Qiang</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Zhang, Jiming</creatorcontrib><creatorcontrib>Xie, Youhua</creatorcontrib><title>Lipid nanoparticle‐mediated delivery of IL‐21‐encoding mRNA induces viral clearance in mouse models of hepatitis B virus persistence</title><title>Journal of medical virology</title><description>Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options cannot effectively induce its clearance. Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS) and identified interleukin‐21 (IL‐21) as a potent inducer of HBV clearance. Lipid nanoparticle (LNP) mediated delivery of mRNA has proven to be a highly safe and effective delivery platform. This work explored the applicability and effectiveness of the mRNA‐LNP platform in IL‐21‐based HBV therapies. First, LNP‐encapsulated murine IL‐21 mRNA (LNP‐IL‐21) was prepared, characterized, and demonstrated to engender IL‐21 expression in vitro and in vivo. Next, LNP‐IL‐21 was shown to induce clearance of both serum and intrahepatic HBV antigen and DNA in two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA), respectively, which was associated with HBV‐specific humoral and cellular immune responses. Furthermore, peripheral blood mononuclear cells from BPS persistence mice treated ex vivo with LNP‐IL‐21 and HBV surface antigen (HBsAg) could induce similar HBV clearance upon infusion into recipient mice. These findings indicated that IL‐21 combined with mRNA‐LNP platform represents a valid and promising strategy for developing novel therapeutics against chronic HBV infection.</description><subject>Animal models</subject><subject>Antigens</subject><subject>Chronic infection</subject><subject>Circular DNA</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B surface antigen</subject><subject>Immune clearance</subject><subject>Immune response (cell-mediated)</subject><subject>Immune response (humoral)</subject><subject>Leukocytes (mononuclear)</subject><subject>Lipids</subject><subject>Nanoparticles</subject><subject>Peripheral blood mononuclear cells</subject><subject>Virology</subject><subject>Viruses</subject><issn>0146-6615</issn><issn>1096-9071</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpdkT1PwzAQhi0EEqUw8A8sscCQcnYSNx5LxUelCiQEc-TYF3CVL-ykUjdmJn4jvwQHmFjO8t2jR6d7CTllMGMA_HJTb2dcguB7ZMJAikjCnO2TCbBEREKw9JAceb8BgExyPiEfa9tZQxvVtJ1yvdUVfr1_1mis6tFQg5XdotvRtqSrdZhwFgo2ujW2eaH14_2C2sYMGj3dWqcqGgTKqUZj6NO6HTyGGjR-VLxip3rbW0-vRnzwtEPnre-DEY_JQakqjyd_75Q831w_Le-i9cPtarlYRzrmaR-hEhlykKmR5RzSUhYZJEJnJuUaVPiAKYSUXBiJLEvjBAohpOCJACxAsnhKzn-9nWvfBvR9XluvsapUg2HfnGcCBJMJywJ69g_dtINrwnYjFQ6YzpNRePFLadd677DMO2dr5XY5g3xMJQ-p5D-pxN92xILM</recordid><startdate>20230901</startdate><enddate>20230901</enddate><creator>Shen, Zhongliang</creator><creator>Zhang, Shenyan</creator><creator>Jiang, Qirong</creator><creator>Liu, Nannan</creator><creator>Li, Fahong</creator><creator>Gao, Zixiang</creator><creator>Pan, Shaokun</creator><creator>Hao, Weiju</creator><creator>Deng, Qiang</creator><creator>Liu, Jing</creator><creator>Zhang, Jiming</creator><creator>Xie, Youhua</creator><general>Wiley Subscription Services, Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2466-3736</orcidid><orcidid>https://orcid.org/0000-0001-8566-9149</orcidid></search><sort><creationdate>20230901</creationdate><title>Lipid nanoparticle‐mediated delivery of IL‐21‐encoding mRNA induces viral clearance in mouse models of hepatitis B virus persistence</title><author>Shen, Zhongliang ; Zhang, Shenyan ; Jiang, Qirong ; Liu, Nannan ; Li, Fahong ; Gao, Zixiang ; Pan, Shaokun ; Hao, Weiju ; Deng, Qiang ; Liu, Jing ; Zhang, Jiming ; Xie, Youhua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c325t-ea68e2095d9f705f9b8046c8d52c0ab800db69926d9e185340b66962460eb0913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animal models</topic><topic>Antigens</topic><topic>Chronic infection</topic><topic>Circular DNA</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatitis B surface antigen</topic><topic>Immune clearance</topic><topic>Immune response (cell-mediated)</topic><topic>Immune response (humoral)</topic><topic>Leukocytes (mononuclear)</topic><topic>Lipids</topic><topic>Nanoparticles</topic><topic>Peripheral blood mononuclear cells</topic><topic>Virology</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shen, Zhongliang</creatorcontrib><creatorcontrib>Zhang, Shenyan</creatorcontrib><creatorcontrib>Jiang, Qirong</creatorcontrib><creatorcontrib>Liu, Nannan</creatorcontrib><creatorcontrib>Li, Fahong</creatorcontrib><creatorcontrib>Gao, Zixiang</creatorcontrib><creatorcontrib>Pan, Shaokun</creatorcontrib><creatorcontrib>Hao, Weiju</creatorcontrib><creatorcontrib>Deng, Qiang</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Zhang, Jiming</creatorcontrib><creatorcontrib>Xie, Youhua</creatorcontrib><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medical virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shen, Zhongliang</au><au>Zhang, Shenyan</au><au>Jiang, Qirong</au><au>Liu, Nannan</au><au>Li, Fahong</au><au>Gao, Zixiang</au><au>Pan, Shaokun</au><au>Hao, Weiju</au><au>Deng, Qiang</au><au>Liu, Jing</au><au>Zhang, Jiming</au><au>Xie, Youhua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lipid nanoparticle‐mediated delivery of IL‐21‐encoding mRNA induces viral clearance in mouse models of hepatitis B virus persistence</atitle><jtitle>Journal of medical virology</jtitle><date>2023-09-01</date><risdate>2023</risdate><volume>95</volume><issue>9</issue><spage>e29062</spage><epage>e29062</epage><pages>e29062-e29062</pages><issn>0146-6615</issn><eissn>1096-9071</eissn><abstract>Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options cannot effectively induce its clearance. Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS) and identified interleukin‐21 (IL‐21) as a potent inducer of HBV clearance. Lipid nanoparticle (LNP) mediated delivery of mRNA has proven to be a highly safe and effective delivery platform. This work explored the applicability and effectiveness of the mRNA‐LNP platform in IL‐21‐based HBV therapies. First, LNP‐encapsulated murine IL‐21 mRNA (LNP‐IL‐21) was prepared, characterized, and demonstrated to engender IL‐21 expression in vitro and in vivo. Next, LNP‐IL‐21 was shown to induce clearance of both serum and intrahepatic HBV antigen and DNA in two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA), respectively, which was associated with HBV‐specific humoral and cellular immune responses. Furthermore, peripheral blood mononuclear cells from BPS persistence mice treated ex vivo with LNP‐IL‐21 and HBV surface antigen (HBsAg) could induce similar HBV clearance upon infusion into recipient mice. These findings indicated that IL‐21 combined with mRNA‐LNP platform represents a valid and promising strategy for developing novel therapeutics against chronic HBV infection.</abstract><cop>London</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1002/jmv.29062</doi><orcidid>https://orcid.org/0000-0002-2466-3736</orcidid><orcidid>https://orcid.org/0000-0001-8566-9149</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animal models Antigens Chronic infection Circular DNA Hepatitis Hepatitis B Hepatitis B surface antigen Immune clearance Immune response (cell-mediated) Immune response (humoral) Leukocytes (mononuclear) Lipids Nanoparticles Peripheral blood mononuclear cells Virology Viruses |
| title | Lipid nanoparticle‐mediated delivery of IL‐21‐encoding mRNA induces viral clearance in mouse models of hepatitis B virus persistence |
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