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Gene editing approaches to eradicate HBV by targeting cccDNA face challenges and limitations due to suboptimal editing efficiency and substantial off\u2010target effects. Herein, a combinatorial therapeutic strategy is developed that integrates CRISPR\/Cas9\u2010mediated cccDNA disruption with an antisense oligonucleotide (ASO)\u2010targeted degradation of pregenomic RNA (pgRNA). To overcome delivery challenges, a hepatocyte\u2010targeting nanocarrier (UACPG) is engineered, featuring low immunogenicity, high payload capacity, and dual\u2010stimuli responsiveness. The UACPG platform enabled liver\u2010specific delivery through surface\u2010conjugated targeting ligands, followed by on\u2010demand release of Cas9 ribonucleoprotein complexes and ASO via RNase H\u2010dependent degradation and near\u2010infrared (NIR) light activation. The results demonstrated that UACPG can effectively reduce HBV replication and viral antigen levels, while significantly lowering cccDNA in hydrodynamic HBV\u2010infected mouse models, with no significant off\u2010target effects observed. This nanocarrier achieved the spatiotemporally controlled release of gene\u2010editing systems in vitro and in vivo, significantly inhibiting the replication of HBV, thereby establishing an innovative technological platform for developing curative HBV therapies.<\/jats:p>","DOI":"10.1002\/adhm.202502835","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T05:18:21Z","timestamp":1759468701000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Galactose\u2010Engineered Dual\u2010Responsive Nanocarrier for ASO\/CRISPR\u2010Cas9 Delivery to Inhibit HBV Replication"],"prefix":"10.1002","volume":"15","author":[{"given":"Liuxian","family":"Chen","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Chongqing Medical University No. 1, Yixueyuan Road Chongqing 400016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Huang","sequence":"additional","affiliation":[{"name":"Bishan Hospital of Chongqing Medical University Bishan Hospital of Chongqing No. 9, Shuangxing Avenue Chong qing 402760 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Chongqing Medical University No. 1, Yixueyuan Road Chongqing 400016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Chongqing Medical University No. 1, Yixueyuan Road Chongqing 400016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yang","sequence":"additional","affiliation":[{"name":"Post\u2010Doctoral Research Center The People's Hospital of Rongchang District No. 3, Guangchang North Road Chongqing 402400 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Chongqing Medical University No. 1, Yixueyuan Road Chongqing 400016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Chongqing Medical University No. 1, Yixueyuan Road Chongqing 400016 China"},{"name":"Yunyang Hospital Chonqqing University of Chinese Medicine No. 618, Beicheng Avenue Chong qing 404500 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4706-926X","authenticated-orcid":false,"given":"Zhenrong","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery Chongqing Key Laboratory of Molecular Oncology and Epigenetics The First Affiliated Hospital of Chongqing Medical University No.1, youyi Road Chongqing 400016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2022.10.008"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00760-9"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00649-z"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15010062"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026623666230413094331"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2018.00054"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c02215"},{"key":"e_1_2_8_8_1","volume":"93","author":"Hu J.","year":"2019","journal-title":"J. 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