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Updated: Oct 25, 2026

Generation of Cationic Nanoliposomes for the Efficient Delivery of In Vitro Transcribed Messenger RNA
Published on: February 1, 2019
Bis(phosphoramidate diester)-Based Ionizable Lipids for Highly Efficient Lung-Selective mRNA Delivery via
Huayu Liu1, Bowen Yang1, Shuye Chen1
1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing211198, China.
Abstract:
Highly efficient lung-selective mRNA delivery is pivotal for advancing mRNA-based targeted therapy. Here, we report bis(phosphoramidate diester)-based ionizable cationic lipids (bpLs) for lung-specific mRNA delivery via a distinct intercellular transport mechanism. A bpL library is synthesized by modular headgroups (Ha), linkers (Lb), and tails (Tc). In vivo screening identifies the formulated bpLH15L2T8/DOPENP as the top lung-selective lipid nanoparticle (LNP) with superior pulmonary mRNA transfection. We elucidate that mononuclear phagocyte-guided cell-to-cell trafficking of bpLH15L2T8/DOPENP contributes to its high efficiency and selectivity of mRNA expression in lung tissue. p53 mRNA (mp53) delivered by bpLH15L2T8/DOPENP restores p53 function in p53-deficient pulmonary metastases and synergizes with immune checkpoint inhibitors to enhance antitumor immunity and inhibit lung metastasis of triple-negative breast cancer (TNBC). An all-trans retinoic acid (ATRA) prodrug-containing bpLNP is further developed for lung-specific codelivery of ATRA and mp53, which effectively suppresses lung metastasis of cancer stem cell-enriched TNBC.
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