Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 16 2 2026 06 15 Chemical Design and Therapeutic Efficacy of HBsAg-Based Nanovaccines for Hepatitis B Virus Clearance: A Preclinical and Clinical Systematic Review 279 290 10.34172/apb.45985 EN Hasti Nequi Marnani https://orcid.org/0009-0007-1415-5803 Tahereh Zadeh Mehrizi https://orcid.org/0009-0003-7277-1103 Babak Eshrati Mehdi Shafiee Ardestani https://orcid.org/0000-0002-0097-9779 Nazanin Ajdary Mohammad Vodjgani Nariman Mosaffa REVIEW 10.34172/apb.45985 2025 07 08 2026 03 12 More than 240 million people worldwide are chronically infected with hepatitis B. Although current antiviral therapies effectively inhibit viral replication, they rarely result in a functional cure. The development of hepatitis B surface antigen (HBsAg)-based nanovaccines has emerged as a potential therapeutic strategy. The aim of this systematic review was to investigate a variety of formulations based on this system and determine their therapeutic efficacy in increasing antibody production, reducing HBsAg and hepatitis B virus DNA levels, stimulating T-cell responses, and reducing hepatitis B nuclear antigen (HBcAg)-positive hepatocytes. Studies published from 2015 to 2025 were included if they assessed the therapeutic benefits of HBsAg-based nanovaccines in animal models of chronic hepatitis B (CHB) or in human patients. A search of the PubMed/Medline, Scopus, and Web of Science databases yielded 361 papers, of which eight, including seven preclinical trials and one clinical trial, satisfied the inclusion criteria. Both HBsAg-containing protein-based and mRNA-based nanovaccines demonstrated a significant ability to increase antibody production, reduce viral markers (HBsAg, HBV DNA, HBcAg, and cccDNA), and induce robust T-cell activation, while maintaining liver enzyme levels (ALT and AST) within the normal range. PreS1-targeting platforms (such as Ferritin NP-preS1) and mRNA-based lipid nanoparticles encoding HBsAg demonstrated enhanced therapeutic efficacy. The well-tolerated εPA-44 liposome vaccines, which were in phase II trials, demonstrated favorable clearance of HBV DNA. In conclusion, HBsAg-based nanovaccines show promising therapeutic potential for CHB by restoring antiviral immunity and reducing viral persistence. Large-scale clinical trials are necessary to confirm their efficacy and long-term safety.