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Accordingly, the hepatitis B virus (HBV) infection can be blocked by inhibiting the binding of the hepatitis B surface pre-S1\/pre-S2 antigen to the hepatocyte receptor NTCP, but the clinical cure rate of pre-S-based vaccines for CHB is limited. Methods: In this study, we designed and prepared multivalent hepatitis B therapeutic mRNA vaccines encoding three hepatitis B surface antigen proteins (L, M, and S) at the cell membrane, verified via in vitro transfection and expression experiments. An in vivo immunization experiment in HBV transgenic (Tg) mice was first completed. Subsequently, an adeno-associated virus plasmid vector carrying the HBV1.2-fold genome (pAAV HBV1.2) model and the adeno-associated virus vector carrying HBV1.3-fold genome (rAAV HBV1.3) model were constructed and immunized with mRNA vaccines. The HBV antigen, antibodies, and HBV DNA in serum were detected. Indirect (enzyme-linked immunosorbent assay) ELISA were made to analyze the activated antigen-specific IgG in HBV Tg mice. Antigen-dependent T-cell activation experiments were carried out, as well as the acute toxicity tests in mice. Results: The L protein\/pre-S antigens could be stably presented at the cell membrane with the support of the S protein (and M protein). After vaccinations, the vaccines effectively reactivated the production of high levels of HBsAb, disrupted immune tolerance, and activated the production of high-affinity antibodies against structural pre-S antigen in HBV Tg mice. The HBsAg seroconversion and serum HBV DNA clearance were achieved in two HBV mice models. Furthermore, pre-S antigen-dependent T-cell response against HBV infection was confirmed. The therapeutic vaccine also showed safety in mice. Conclusions: A novel therapeutic mRNA vaccine was developed to break through HBsAg-mediated immune tolerance and treat CHB by stably presenting the pre-S antigen at the membrane, and the vaccine has great potential for the functional cure of CHB.<\/jats:p>","DOI":"10.3390\/pharmaceutics17020211","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T04:00:28Z","timestamp":1738900828000},"page":"211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Multivalent mRNA Therapeutic Vaccine Exhibits Breakthroughs in Immune Tolerance and Virological Suppression of HBV by Stably Presenting the Pre-S Antigen on the Cell Membrane"],"prefix":"10.3390","volume":"17","author":[{"given":"Shang","family":"Liu","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Du","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenguo","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Cell Tech Medical Research Institute Co., Ltd., Nanjing 211100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongchen","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingtao","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijia","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"},{"name":"Jiangsu Cell Tech Medical Research Institute Co., Ltd., Nanjing 211100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9193-2019","authenticated-orcid":false,"given":"Hongping","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S2468-1253(22)00341-7","article-title":"New hepatitis B drug development disillusions: Time to reset?","volume":"8","author":"Pawlotsky","year":"2023","journal-title":"Lancet Gastroenterol. 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