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The discovery of novel ionizable lipids relies on combinatorial chemistry synthesis and screening. However, current libraries mainly focus on optimizing amine cores and hydrophobic tails, often neglecting linker optimization, which restricts novel ionizable lipid discovery. To address this, a one\u2010pot, two\u2010step, three\u2010component reaction based on N\u2010hydroxysuccinimide\u2010ester\u2010maleimide bispecific linkers is first developed for constructing combinatorial libraries. Two libraries containing 344 thiosuccinimide lipids are synthesized. Through in vitro and in vivo screening, it is discovered that thiosuccinimide lipids with different types of linkers exhibit different organ tropism. On this basis, T\n                    <jats:sub>3<\/jats:sub>\n                    A\u2010L5\u20102C\n                    <jats:sub>10<\/jats:sub>\n                    derived from an alkyl chain\u2010based bispecific linker is identified as a lead lipid. When encapsulating mRNA encoding luciferase, T\n                    <jats:sub>3<\/jats:sub>\n                    A\u2010L5\u20102C\n                    <jats:sub>10<\/jats:sub>\n                    LNP achieved 12\u2010, 9.8\u2010, and 44.7\u2010fold higher luciferase expression compared to the commercial lipids DLin\u2010MC3\u2010DMA, ALC\u20100315, and Lipid 5, respectively. Furthermore, when co\u2010delivering Cas9 mRNA and sgRNA targeting proprotein convertase subtilisin\/kexin type 9, T\n                    <jats:sub>3<\/jats:sub>\n                    A\u2010L5\u20102C\n                    <jats:sub>10<\/jats:sub>\n                    LNP demonstrated 62\u2010fold and 33\u2010fold greater gene editing efficiency than DLin\u2010MC3\u2010DMA and ALC\u20100315 LNPs, respectively. These results highlight the great promise of T\n                    <jats:sub>3<\/jats:sub>\n                    A\u2010L5\u20102C\n                    <jats:sub>10<\/jats:sub>\n                    for the delivery of mRNA\u2010based therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202502225","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T04:18:16Z","timestamp":1761625096000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthesis and Screening of Bispecific Linker\u2010based Combinatorial Libraries Identified Thiosuccinimide Lipids for mRNA Delivery"],"prefix":"10.1002","volume":"15","author":[{"given":"Qiang","family":"Liu","sequence":"first","affiliation":[{"name":"Beijing Life Science Academy  Beijing 102209 China"},{"name":"New Cornerstone Science Laboratory Department of Chemistry Key Laboratory of Bioorganic Phosphorus Chemistry &amp; Chemical Biology Tsinghua University  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"New Cornerstone Science Laboratory Department of Chemistry Key Laboratory of Bioorganic Phosphorus Chemistry &amp; Chemical Biology Tsinghua University  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Guo","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy  Beijing 102209 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junlin","family":"Sun","sequence":"additional","affiliation":[{"name":"New Cornerstone Science Laboratory Department of Chemistry Key Laboratory of Bioorganic Phosphorus Chemistry &amp; Chemical Biology Tsinghua University  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zijian","family":"Pan","sequence":"additional","affiliation":[{"name":"New Cornerstone Science Laboratory Department of Chemistry Key Laboratory of Bioorganic Phosphorus Chemistry &amp; Chemical Biology Tsinghua University  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sen","family":"Lin","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy  Beijing 102209 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiyu","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of general surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China  Hefei 230001 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianyu","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of general surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China  Hefei 230001 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy  Beijing 102209 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningqiang","family":"Gong","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy  Beijing 102209 China"},{"name":"Department of general surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China  Hefei 230001 China"},{"name":"Center for BioAnalytical Chemistry Hefei National Laboratory of Physical Science at Microscale University of Science and Technology of China  Hefei 230026 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0750-7352","authenticated-orcid":false,"given":"Jinghong","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Life Science Academy  Beijing 102209 China"},{"name":"New Cornerstone Science Laboratory Department of Chemistry Key Laboratory of Bioorganic Phosphorus Chemistry &amp; 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