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While the current efficient version of adenine base editors (ABEs), such as ABE8e, exhibits exceptional efficiency for A\u2010to\u2010G conversions, their clinical translation is hindered by persistent high off\u2010target editing effects. Here, we applied artificial intelligence\u2010assisted design a safe ABE variant, RDLot\u2010ABE, with a narrow(4\u00a0nt) editing window and substantially lower DNA off\u2010target editing activity compared to ABE8e. Moreover, targeted knockdown of\n                    <jats:italic>Fscn1<\/jats:italic>\n                    for osteoarthritis treatment using RDLot\u2010ABE alleviates cartilage degradation in explants derived from human patients. Notably, intra\u2010articular delivery of the RDLot\u2010ABE to reduce\n                    <jats:italic>Fscn1<\/jats:italic>\n                    effectively arrests disease progression in a murine osteoarthritis model. These findings establish RDLot\u2010ABE as a safe and precise tool, expanding the clinical potential of gene editing therapies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202519807","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:42:32Z","timestamp":1777452152000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design of Safe and Efficient Adenine Base Editors via Protein Language Model Screening for Osteoarthritis Treatment"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiawei","family":"Yao","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases The Third Affiliated Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1947-7463","authenticated-orcid":false,"given":"Dalin","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases The Third Affiliated Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences &amp; Peking Union Medical College Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxuan","family":"Ren","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences &amp; Peking Union Medical College Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengcheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases The Third Affiliated Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfang","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases The Third Affiliated Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Shang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences &amp; Peking Union Medical College Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases The Third Affiliated Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinuo","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences &amp; Peking Union Medical College Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su'an","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Spinal Surgery, Orthopedic Medical Center Zhujiang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases The Third Affiliated Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences &amp; Peking Union Medical College Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9798-834X","authenticated-orcid":false,"given":"Xiaogang","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases The Third Affiliated Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2031054"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003609\u2010w"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010022\u201002190\u20107"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk9428"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010biochem\u2010052521\u2010013938"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010020\u20100453\u2010z"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2504747"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3803"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010022\u201001163\u20108"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010021\u201000943\u20102"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/procel\/pwag006"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201036887\u20101"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202309004"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201052483\u20103"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac201"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010019\u20100134\u2010y"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010020\u20100491\u20106"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2574"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413\u2010024\u201000357\u20101"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201065311\u2010z"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb1390"},{"key":"e_1_2_10_23_1","volume-title":"International Conference on Learning Representations(ICLR2022)","author":"Hu E. 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