Oligonucleotide and RNA-targeted therapeutics for chronic hepatitis B: Antigen reduction, delivery, and functional cure strategies
4 affiliations
- 1Central Laboratory, Affiliated Hospital of Yunnan University, Kunming, Yunnan Province 650203, China; School of Medicine, Yunnan University, Kunming 650091, China
- 2Central Laboratory, Affiliated Hospital of Yunnan University, Kunming, Yunnan Province 650203, China
- 3Department of Infectious Diseases and Hepatology, Affiliated Hospital of Yunnan University, Kunming, Yunnan Province 650203, China; Corresponding author: Prof. Hui Li, Department of Infectious Diseases and Hepatology, Affiliated Hospital of Yunnan University, Kunming, Yunnan Province 650203, China.
- 4Central Laboratory, Affiliated Hospital of Yunnan University, Kunming, Yunnan Province 650203, China; School of Medicine, Yunnan University, Kunming 650091, China; Corresponding author: Dr. Taicheng Zhou, Central Laboratory, Affiliated Hospital of Yunnan University, Kunming, Yunnan Province 650203, China.
Abstract
Chronic hepatitis B (CHB) remains difficult to cure because nucleos(t)ide analogs suppress hepatitis B virus (HBV) replication but do not eliminate covalently closed circular DNA (cccDNA) or integrated HBV DNA, which sustain viral RNA and hepatitis B surface antigen (HBsAg) production. RNA-targeted therapeutics, including small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and CRISPR-Cas13 platforms, offer sequence-directed approaches to suppress HBV transcripts and reduce antigen burden. Clinical evaluation of emerging HBV-directed therapies, including JNJ-3989, bepirovirsen, imdusiran, and related candidates, has demonstrated meaningful declines in circulating HBsAg levels. The recent phase III B-Well data further support the role of ASO-mediated antigen reduction as a potential therapeutic approach to increase the likelihood of functional cure within finite treatment regimens for selected patients. However, therapeutically induced HBsAg reduction alone rarely guarantees durable off-treatment control. This review summarizes HBV-directed RNA and oligonucleotide therapeutics from a translational pharmacology perspective, emphasizing transcript-silencing mechanisms, delivery constraints, pharmacodynamic endpoints, safety considerations, biomarker-guided patient selection, and integration with nucleos(t)ide analogs and immunomodulatory interventions. We propose that RNA-mediated antigen reduction may support finite therapy in biomarker-selected patients and may also serve as an antigen-conditioning component within staged functional cure strategies.
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BibTeX
@article{meng2026oligonucleotide,
title = {{Oligonucleotide and RNA-targeted therapeutics for chronic hepatitis B: Antigen reduction, delivery, and functional cure strategies}},
author = {Xingchen Meng and Faisal Mahmood and Hui Li and Taicheng Zhou},
journal = {Molecular Therapy: Nucleic Acids},
year = {2026},
month = oct,
doi = {10.1016/j.omtn.2026.103125},
url = {https://doi.org/10.1016/j.omtn.2026.103125},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Oligonucleotide and RNA-targeted therapeutics for chronic hepatitis B: Antigen reduction, delivery, and functional cure strategies
AU - Xingchen Meng
AU - Faisal Mahmood
AU - Hui Li
AU - Taicheng Zhou
PY - 2026
DA - 2026/10/01
JO - Molecular Therapy: Nucleic Acids
DO - 10.1016/j.omtn.2026.103125
UR - https://doi.org/10.1016/j.omtn.2026.103125
AB - Chronic hepatitis B (CHB) remains difficult to cure because nucleos(t)ide analogs suppress hepatitis B virus (HBV) replication but do not eliminate covalently closed circular DNA (cccDNA) or integrated HBV DNA, which sustain viral RNA and hepatitis B surface antigen (HBsAg) production. RNA-targeted therapeutics, including small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and CRISPR-Cas13 platforms, offer sequence-directed approaches to suppress HBV transcripts and reduce antigen burden. Clinical evaluation of emerging HBV-directed therapies, including JNJ-3989, bepirovirsen, imdusiran, and related candidates, has demonstrated meaningful declines in circulating HBsAg levels. The recent phase III B-Well data further support the role of ASO-mediated antigen reduction as a potential therapeutic approach to increase the likelihood of functional cure within finite treatment regimens for selected patients. However, therapeutically induced HBsAg reduction alone rarely guarantees durable off-treatment control. This review summarizes HBV-directed RNA and oligonucleotide therapeutics from a translational pharmacology perspective, emphasizing transcript-silencing mechanisms, delivery constraints, pharmacodynamic endpoints, safety considerations, biomarker-guided patient selection, and integration with nucleos(t)ide analogs and immunomodulatory interventions. We propose that RNA-mediated antigen reduction may support finite therapy in biomarker-selected patients and may also serve as an antigen-conditioning component within staged functional cure strategies.
SN - 2162-2531
ER -