Bis(phosphoramidate diester)-Based Ionizable Lipids for Highly Efficient Lung-Selective mRNA Delivery via Intercellular Transport.

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.