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Nowadays, several drugs are used to treat chronic hepatitis B; however, full healing remains controversial. The viral covalently closed circular DNA (cccDNA) formed by HBV forms a major challenge in its treatment, as does the ability of HBV to integrate itself into the host genome, which enables infection reactivation. Interfering RNA (RNAi) is a gene-silencing post-transcriptional mechanism which forms as a promising alternative to treat chronic hepatitis B. The aim of the present review is to assess the evolution of hepatitis B treatment approaches based on using RNA interference. Methods: Data published between 2016 and 2023 in scientific databases (PubMed, PMC, LILACS, and Bireme) were assessed. Results: In total, 76,949 articles were initially identified and quality-checked, and 226 eligible reports were analyzed in depth. The main genomic targets, delivery systems, and major HBV therapy innovations are discussed in this review. This review reinforces the therapeutic potential of RNAi and identifies the need for conducting further studies to fill the remaining gaps between bench and clinical practice.<\/jats:p>","DOI":"10.3390\/v16111710","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T06:55:37Z","timestamp":1730357737000},"page":"1710","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evaluation of Interfering RNA Efficacy in Treating Hepatitis B: Is It Promising?"],"prefix":"10.3390","volume":"16","author":[{"given":"Giovana Paula","family":"Angelice","sequence":"first","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9670-1502","authenticated-orcid":false,"given":"Pedro Henrique","family":"Roque","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Valente","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Galv\u00e3o","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7644-8969","authenticated-orcid":false,"given":"Livia Melo","family":"Villar","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7705-5921","authenticated-orcid":false,"given":"Vinicius Motta","family":"Mello","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco C. A.","family":"Mello","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e1rbara Vieira","family":"Lago","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1099\/jgv.0.001415","article-title":"ICTV Virus Taxonomy Profile: Hepadnaviridae","volume":"101","author":"Magnius","year":"2020","journal-title":"J. Gen. Virol."},{"key":"ref_2","unstructured":"(2023, October 18). World Health Organization (WHO) 2023, Hepatitis B. 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