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Recently, poly(\u03b2\u2010amino esters) (PBAEs) have emerged as promising carriers for non\u2010viral gene delivery due to their tunable structures and high delivery efficiency. Nonetheless, the cationic nature of PBAEs raises toxicity concerns, and their lack of tissue\u2010specific targeting capability limits their clinical application. Herein, a novel PBAE for efficient plasmid delivery is constructed, which contains disulfide bonds in the backbone and N\u2010acetylgalactosamine (GalNAc) moieties at the terminals (GalNAc\u2010PBAEs). To address the potential reduction in nucleic acid condensing capacity caused by end\u2010capping PBAE with GalNAc, the commonly used end\u2010capping amines in conventional PBAE are employed as monomers to create GalNAc\u2010PBAEs with tertiary amine side chains. Through side\u2010chain screening, the optimized GalNAc\u2010PBAE exhibits enhanced transfection efficiency, surpassing that of the conventional top\u2010performing PBAE, C28\u2010E7, and rivaling the commercial transfection reagent Lipo2000. Importantly, the GalNAc moieties enable the plasmid\u2010PBAE polyplex to efficiently target the liver. In a mouse model with acute liver fibrosis, the efficient delivery and expression of a representative plasmid encoding HGF significantly mitigate liver fibrosis and improve liver function, demonstrating the potential of the designed PBAE in gene therapy.<\/jats:p>","DOI":"10.1002\/smtd.202401286","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T09:58:08Z","timestamp":1741687088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["GalNAc End\u2010Capped Poly(\u03b2\u2010amino ester)s with Screened Side Chains for Efficient Gene Delivery"],"prefix":"10.1002","volume":"9","author":[{"given":"Xinlong","family":"Liu","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimeng","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinhua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiology Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Jiao Tong University School of Medicine  600 Yi Shan Road Shanghai 200233 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangyang","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fujun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiafeng","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqi","family":"Guo","sequence":"additional","affiliation":[{"name":"Henan Provincial People's Hospital People's Hospital of Zhengzhou University Engineering Research Center for Gynecological Oncology Nanomedicine of Henan Province  Zhengzhou Henan 450003 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine Renji Hospital School of Medicine Shanghai Jiao Tong University  Shanghai 200217 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9311-0799","authenticated-orcid":false,"given":"Chuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01589-z"},{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1152"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.03.021"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-012017-043332"},{"key":"e_1_2_8_2_3","doi-asserted-by":"publisher","DOI":"10.31635\/ccschem.020.201900084"},{"key":"e_1_2_8_2_4","doi-asserted-by":"publisher","DOI":"10.31635\/ccschem.021.202101029"},{"key":"e_1_2_8_3_1","first-page":"664","volume":"6","author":"Bulcha J. 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