Thiourea‐Functionalized Ionizable Lipids Enable Systemic mRNA Delivery to Secondary Lymphoid Organs and Dual‐Modal Lymphatic Metastasis Imaging

Abstract Systemic delivery of messenger RNA (mRNA) to non‐hepatocytes using lipid nanoparticles (LNPs) remains challenging. Inspired by anion coordination chemistry, here we report the rational chemical design of thiourea‐functionalized ionizable lipids (TUILs) for delivering mRNA potently and specifically to the secondary lymphoid organs (SLOs). The leading TUIL, namely 4A3‐LNSC8, features an impressive thiourea‐based linker capable of binding with various halide anions (F − , Cl − , I − ) through hydrogen‐bonding interaction, enabling precise regulation of LNP organotropism in vivo. When administered systemically, the representative Cl‐4A3‐LNSC8 LNPs exclusively redirected mRNA delivery from the liver to SLOs, yielding a 65‐fold and 29‐fold increase in splenic mRNA expression compared to DLin‐MC3‐DMA and SM102 LNPs with the addition of anionic lipid (18PA). Notably, upon intravenous injection of 0.2 mg kg −1 Cre mRNA, Cl‐4A3‐LNSC8 LNPs demonstrated strong tropism for splenic macrophages with high gene editing efficiency up to 65.7%, outperforming the current state‐of‐the‐art spleen‐targeted LNPs. Moreover, by leveraging iodine's CT contrast properties, I‐4A3‐LNSC8 LNPs mediated efficient theranostic mRNA delivery to lymph nodes, allowing early detection of lymphatic metastasis via dual‐modal CT and bioluminescence imaging. This work provides new insights into the development of cell‐specific ionizable lipids, advancing future applications of macrophage‐targeted therapies.