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Lipid nanoparticle-mediated delivery of mRNA for IL-21 achieves clearance of hepatitis B virus in mouse models
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  • Zhongliang Shen,
  • Shenyan Zhang,
  • Nannan Liu,
  • Qirong Jiang,
  • Zixiang Gao,
  • Weiju Hao,
  • Qiang Deng,
  • Jing Liu,
  • Jiming Zhang,
  • You-hua Xie
Zhongliang Shen
Huashan Hospital Fudan University Department of Infectious Diseases

Corresponding Author:shenzhongliangnjnu@163.com

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Shenyan Zhang
Huashan Hospital Fudan University Department of Infectious Diseases
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Nannan Liu
Fudan University School of Basic Medical Sciences
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Qirong Jiang
Huashan Hospital Fudan University Department of Infectious Diseases
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Zixiang Gao
Fudan University School of Basic Medical Sciences
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Weiju Hao
University of Shanghai for Science and Technology
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Qiang Deng
Fudan University School of Basic Medical Sciences
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Jing Liu
Fudan University School of Basic Medical Sciences
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Jiming Zhang
Huashan Hospital Fudan University Department of Infectious Diseases
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You-hua Xie
Huashan Hospital Fudan University Department of Infectious Diseases
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Abstract

Chronic hepatitis B virus (HBV) infection causes hepatitis, liver cirrhosis and hepatocellular carcinoma. Covalently closed circular DNA (cccDNA) is the transcription template for HBV RNAs and not affected by current treatment options. Effective therapeutics with ability to remove cccDNA need to be developed. Previously, we established an HBV persistence mouse model via hydrodynamic injection of a clinical isolate (BPS) and identified IL-21 as a potent inducer of viral clearance. Here, we aimed to explore the anti-HBV effects of IL-21 messenger RNA (mRNA) delivered by lipid nanoparticle (LNP-IL-21) system. First, LNP-IL-21 was prepared and analyzed for its safety, expression, biodistribution and stability in vitro and in vivo. Next, LNP-IL-21 was injected into two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA) respectively. LNP-IL-21 administration successfully cleared HBV serum markers, and more importantly, BPS replicons and rcccDNA in livers, which was associated with activation of viral specific immune responses. Notably, transfer of peripheral blood mononuclear cells from BPS persistence mice stimulated ex vivo with LNP-IL-21 and viral antigen could induce HBV clearance in recipient mice. These findings suggested that both LNP-IL-21-based gene and cellular therapies provided novel therapeutic strategies against chronic HBV infection.
15 Mar 2023Submitted to Journal of Medical Virology
17 Mar 2023Submission Checks Completed
17 Mar 2023Assigned to Editor
17 Mar 2023Review(s) Completed, Editorial Evaluation Pending
18 Mar 2023Reviewer(s) Assigned
19 Apr 2023Editorial Decision: Revise Major
20 Jul 20231st Revision Received
07 Aug 2023Submission Checks Completed
07 Aug 2023Assigned to Editor
07 Aug 2023Review(s) Completed, Editorial Evaluation Pending
08 Aug 2023Reviewer(s) Assigned
18 Aug 2023Editorial Decision: Accept