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Inspired by anion coordination chemistry, here we report the rational chemical design of thiourea\u2010functionalized ionizable lipids (TUILs) for delivering mRNA potently and specifically to the secondary lymphoid organs (SLOs). The leading TUIL, namely 4A3\u2010LNSC8, features an impressive thiourea\u2010based linker capable of binding with various halide anions (F\n                    <jats:sup>\u2212<\/jats:sup>\n                    , Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    , I\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) through hydrogen\u2010bonding interaction, enabling precise regulation of LNP organotropism in vivo. When administered systemically, the representative Cl\u20104A3\u2010LNSC8 LNPs exclusively redirected mRNA delivery from the liver to SLOs, yielding a 65\u2010fold and 29\u2010fold increase in splenic mRNA expression compared to DLin\u2010MC3\u2010DMA and SM102 LNPs with the addition of anionic lipid (18PA). Notably, upon intravenous injection of 0.2\u00a0mg kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    Cre mRNA, Cl\u20104A3\u2010LNSC8 LNPs demonstrated strong tropism for splenic macrophages with high gene editing efficiency up to 65.7%, outperforming the current state\u2010of\u2010the\u2010art spleen\u2010targeted LNPs. Moreover, by leveraging iodine's CT contrast properties, I\u20104A3\u2010LNSC8 LNPs mediated efficient theranostic mRNA delivery to lymph nodes, allowing early detection of lymphatic metastasis via dual\u2010modal CT and bioluminescence imaging. This work provides new insights into the development of cell\u2010specific ionizable lipids, advancing future applications of macrophage\u2010targeted therapies.\n                  <\/jats:p>","DOI":"10.1002\/anie.202523579","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T14:02:49Z","timestamp":1768053769000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Thiourea\u2010Functionalized Ionizable Lipids Enable Systemic mRNA Delivery to Secondary Lymphoid Organs and Dual\u2010Modal Lymphatic Metastasis Imaging"],"prefix":"10.1002","volume":"65","author":[{"given":"Zhaoming","family":"Chen","sequence":"first","affiliation":[{"name":"Research Center for Analytical Sciences Tianjin Key Laboratory of Biosensing and Molecular Recognition Frontiers Science Center for New Organic Matter College of Chemistry, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Tianjin Key Laboratory of Biosensing and Molecular Recognition Frontiers Science Center for New Organic Matter College of Chemistry, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingbing","family":"Zheng","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Tianjin Key Laboratory of Biosensing and Molecular Recognition Frontiers Science Center for New Organic Matter College of Chemistry, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuexia","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Tianjin Key Laboratory of Biosensing and Molecular Recognition Frontiers Science Center for New Organic Matter College of Chemistry, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Tianjin Key Laboratory of Biosensing and Molecular Recognition Frontiers Science Center for New Organic Matter College of Chemistry, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology Tianjin Key Laboratory of Protein Science College of Life Sciences, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology Tianjin Key Laboratory of Protein Science College of Life Sciences, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4969-8158","authenticated-orcid":false,"given":"Hu","family":"Xiong","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Tianjin Key Laboratory of Biosensing and Molecular Recognition Frontiers Science Center for New Organic Matter College of Chemistry, Nankai University  94 Weijin Road, Nankai District Tianjin 300071 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