mRNA vaccines for HBV: Mechanisms, preclinical advances, and therapeutic clinical progress

Hepatitis B virus (HBV) remains a leading cause of cirrhosis and hepatocellular carcinoma, while functionally curative therapies remain scarce. Durable remission is hindered by the persistence of covalently closed circular DNA (cccDNA) and viral genome integration, both of which contribute to impaired immune responses. mRNA-based technologies provide a versatile platform for prevention and treatment, owing to their rapid development cycle and intrinsic immunostimulatory properties. In preclinical HBV-carrier mouse models, lipid-nanoparticle (LNP) mRNA vaccines encoding hepatitis B surface antigen (HBsAg) or polyvalent Ags have achieved HBsAg clearance and HBV-DNA reduction, outperforming protein-based comparators. Clinically, two phase I therapeutic trials have been initiated to date. An ARCUS nuclease delivered as LNP-mRNA entered first-in-human testing in 2025, with only preliminary safety data available from a small patient cohort and no published efficacy data. Similarly, HBx-biased mRNA vaccines, such as WGc-0201, have recently entered early clinical evaluation without reported clinical efficacy. Despite these advances, several challenges impede effective therapy, including innate-immune overactivation, HBV genotypic diversity, and the need for rational therapeutic combinations. This review summarizes current preclinical findings and emerging clinical evidence and outlines future strategies toward durable viral control and effective prophylaxis, including self-amplifying or cyclic RNAs, receptor-targeted LNPs, and multimodal therapeutic regimens.