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Many groups have reported success instilling liquid mRNA formulations in animal models, but direct intratracheal administration of large liquid quantities to the human lung presents significant safety and distribution concerns. To accomplish safe and effective mRNA delivery to the lung, formulations must be prepared for dosing via inhalation. An inhaled mRNA delivery system for the lung must be both robust enough to survive inhalation conditions and potent enough to deliver mRNA upon reaching the lung. In this work dry powder lipid nanoparticle formulations are developed, using spray\u2010freeze\u2010drying, to produce stable, biologically active, inhalable dry powders for mRNA delivery. The final powders have suitable aerosolization properties, with mean mass aerodynamic diameter (MMAD) of 3\u20134 microns, and fine particle fraction (FPF) \u224840%, allowing for efficient mRNA delivery to the deep lung following inhalation. Importantly, the formulations developed here are suitable for use with different ionizable lipids. Four different ionizable lipid\u2010based formulations are evaluated as powders, and all exhibit in vivo pulmonary mRNA delivery equal to that of instilled liquid formulations. These results lay promising groundwork for the eventual development of an inhalable mRNA dry powder therapeutic.<\/jats:p>","DOI":"10.1002\/adhm.202400509","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T08:04:59Z","timestamp":1727769899000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Inhalable Dry Powders for Lung mRNA Delivery"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6679-2974","authenticated-orcid":false,"given":"Akiva","family":"Gordon","sequence":"first","affiliation":[{"name":"David H Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Department of Chemical Engineering Massachusetts Institute of Technology  Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Li","sequence":"additional","affiliation":[{"name":"David H Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Department of Chemical Engineering Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"},{"name":"Institute of Biomedical Engineering University of Toronto  Toronto Ontario Canada"},{"name":"Department of Chemistry University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-5999","authenticated-orcid":false,"given":"Jacob","family":"Witten","sequence":"additional","affiliation":[{"name":"David H Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Department of Chemical Engineering Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Department of Biological Engineering Massachusetts Institute of Technology  Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"David H Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Department of Chemical Engineering Massachusetts Institute of Technology  Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5629-4798","authenticated-orcid":false,"given":"Daniel G.","family":"Anderson","sequence":"additional","affiliation":[{"name":"David H Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Department of Chemical Engineering Massachusetts Institute of Technology  Cambridge MA 02139 USA"},{"name":"Department of Anesthesiology Boston Children's Hospital  Boston MA 02115 USA"},{"name":"Department of Statistics University of Michigan  Ann Arbor USA"},{"name":"Harvard and MIT Division of Health Science and Technology Massachusetts Institute of Technology  Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,1]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034577"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035389"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-020-0159-8"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade6967"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.3c00304"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.2c21683"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/SCIADV.ABJ6901"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202006619"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01679-x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01824-6"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00576-6"},{"key":"e_1_2_8_12_1","author":"Stoller J. 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