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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.<\/jats:p>","DOI":"10.1021\/acs.nanolett.6c02802","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:02:00Z","timestamp":1790604120000},"page":"13335-13347","source":"Crossref","is-referenced-by-count":0,"title":["Bis(phosphoramidate\ndiester)-Based Ionizable Lipids\nfor Highly Efficient Lung-Selective mRNA Delivery via Intercellular\nTransport"],"prefix":"10.1021","volume":"26","author":[{"given":"Huayu","family":"Liu","sequence":"first","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Yang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuye","family":"Chen","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikun","family":"Li","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0043-3938","authenticated-orcid":true,"given":"Yifei","family":"Huang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Xing","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Liu","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sida","family":"Jiang","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4010-8879","authenticated-orcid":true,"given":"Ran","family":"Mo","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , ,","place":["Nanjing, China, 211198"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"10432","key":"2026100710095914400_cit1","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1016\/S0140-6736(23)02444-3","article-title":"mRNA-based therapeutics:\nlooking beyond COVID-19 vaccines","volume":"403","author":"Parhiz","year":"2024","journal-title":"Lancet"},{"issue":"11","key":"2026100710095914400_cit2","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1038\/s41587-022-01491-z","article-title":"Unlocking\nthe promise of mRNA therapeutics","volume":"40","author":"Rohner","year":"2022","journal-title":"Nat. Biotechnol."},{"issue":"11","key":"2026100710095914400_cit3","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1038\/s41591-022-02061-1","article-title":"The landscape of mRNA nanomedicine","volume":"28","author":"Huang","year":"2022","journal-title":"Nat. Med."},{"issue":"9","key":"2026100710095914400_cit4","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/s41573-024-00977-6","article-title":"The 60-year evolution of lipid nanoparticles for nucleic\nacid delivery","volume":"23","author":"Cullis","year":"2024","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"11","key":"2026100710095914400_cit5","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1038\/s41573-024-01042-y","article-title":"mRNA vaccines for infectious diseases - advances, challenges\nand opportunities","volume":"23","author":"Pardi","year":"2024","journal-title":"Nat. Rev. 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