Data availability<\/h2>\n
Illumina Sequencing data have been submitted to the Sequence Read Archive; these datasets are available under BioProject Accession no. PRJNA918691<\/a> (ref. 37<\/a><\/sup>). The authors declare that all other data supporting the findings of this study are available within the paper and its Supplementary Information<\/a> files or on reasonable request. Plasmids are available from Addgene.<\/p>\n<\/div>\n Rudnick, D. A. & Perlmutter, D. H. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology<\/i> 42<\/b>, 514\u2013521 (2005).<\/p>\n Article<\/a>\u00a0 Riordan, J. R. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science<\/i> 245<\/b>, 1066\u20131073 (1989).<\/p>\n Article<\/a>\u00a0 Kwok, A. J., Mentzer, A. & Knight, J. C. Host genetics and infectious disease: new tools, insights and translational opportunities. Nat. Rev. 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B.L., R.S.M., A.G. and A.J. were supported by Translate Bio. B.L. was supported by the Leslie Dan Faculty of Pharmacy startup fund, the Connaught Fund (no. 514681), the J. P. Bickell Foundation (grant no. 515159), the Canada Research Chairs Program (no. CRC-2022-00575), Canadian Institutes of Health Research (no. PJH-185722) and the Canada Foundation for Innovation John R. Evans Leaders Fund (no. 43711). A.V. was supported by the PRiME Postdoctoral Fellowship from the University of Toronto. S.P.L., G.G., W.X. and D.A. were supported by grants from the National Institutes of Health (nos. UG3HL147367 and UH3HL147367). W.X. was supported by grants from the National Institutes of Health (nos. DP2HL137167 and P01HL131471), the American Cancer Society (grant no. 129056-RSG-16-093) and the Cystic Fibrosis Foundation. We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically the Animal Imaging & Preclinical Testing, Histology, Nanotechnology Materials and Microscopy core facilities.<\/p>\n<\/div>\n Author notes<\/span><\/p>\n These authors contributed equally: Bowen Li, Rajith Singh Manan, Shun-Qing Liang.<\/p>\n<\/li>\n<\/ol>\n David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA<\/p>\n Bowen Li,\u00a0Rajith Singh Manan,\u00a0Akiva Gordon,\u00a0Allen Jiang,\u00a0Robert Langer\u00a0&\u00a0Daniel Anderson<\/p>\n<\/li>\n Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA<\/p>\n Bowen Li,\u00a0Rajith Singh Manan,\u00a0Akiva Gordon,\u00a0Allen Jiang,\u00a0Robert Langer\u00a0&\u00a0Daniel Anderson<\/p>\n<\/li>\n Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada<\/p>\n Bowen Li\u00a0&\u00a0Andrew Varley<\/p>\n<\/li>\n Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada<\/p>\n Bowen Li<\/p>\n<\/li>\n RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA<\/p>\n Shun-Qing Liang,\u00a0Guangping Gao\u00a0&\u00a0Wen Xue<\/p>\n<\/li>\n Horae Gene Therapy Center and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA<\/p>\n Guangping Gao<\/p>\n<\/li>\n Department of Anesthesiology, Boston Children\u2019s Hospital, Boston, MA, USA<\/p>\n Robert Langer\u00a0&\u00a0Daniel Anderson<\/p>\n<\/li>\n Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA<\/p>\n Robert Langer\u00a0&\u00a0Daniel Anderson<\/p>\n<\/li>\n Harvard\u2013MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA<\/p>\n Robert Langer\u00a0&\u00a0Daniel Anderson<\/p>\n<\/li>\n Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA<\/p>\n Wen Xue<\/p>\n<\/li>\n<\/ol>\n B.L., R.S.M. and S.Q.L. conceived the project and wrote the paper, with input from all authors. B.L. and R.S.M. designed the combinatorial lipid library. B.L., R.S.M., S.Q.L., A.G. and A.J. performed experiments and analyzed data. B.L., R.S.M. and S.Q.L. wrote the paper. B.L., S.Q.L., A.V., W.X. and D.G.A. discussed the results and edited the paper. G.G., R.L., W.X. and D.A. acquired funding and supervised the project.<\/p>\n Correspondence to B.L., R.S.M., A.G. and D.A. have filed a patent (PCT\/US2022\/052314) for development of the described lipids. D.A. receives research funding from Translate Bio and is a Founder of Orna Therapeutics. R.L. is a cofounder of Moderna; he also serves on the board and has equity in Particles for Humanity. For a list of entities with which R.L. is, or has been, recently involved, compensated or uncompensated, see https:\/\/www.dropbox.com\/s\/yc3xqb5s8s94v7x\/Rev%20Langer%20COI.pdf?dl=0<\/a>. The other authors declare no competing interests.<\/p>\n<\/p><\/div>\n<\/div>\n Nature Biotechnology<\/i> thanks H. L. Wong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.<\/p>\n<\/p><\/div>\n<\/div>\n Publisher\u2019s note<\/b> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.<\/p>\n<\/div>\n Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.<\/p>\nReferences<\/h2>\n
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\n Google Scholar<\/a>\u00a0\n <\/p>\n<\/li>\nAcknowledgements<\/h2>\n
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