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However, saRNA and the lipid nanoparticles (LNPs) used for their delivery activate the innate immune system, which may complicate pulmonary delivery of saRNA-LNPs. In this study, we demonstrated that intratracheal administration of saRNA-LNPs can cause significant side effects that can be linked to innate immune cell recruitment and cytokine release in the lungs. However, through systematic optimization of the LNP formulation and the saRNA dose, we could restrict the inflammation in the lungs to an acceptable level. With these optimized saRNA-LNPs, high levels of transgene expression were achieved in the lungs of mice that lasted for at least 21 days. Moreover, intratracheal delivery of optimized saRNA-LNPs encoding SARS-CoV-2 nanobodies resulted in detectable nanobody levels in the lungs.<\/jats:p>","DOI":"10.1021\/acsnano.6c00709","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T02:53:28Z","timestamp":1784343208000},"page":"21022-21038","source":"Crossref","is-referenced-by-count":0,"title":["Pulmonary Delivery\nof Self-Amplifying RNA: Balancing\nInflammation and Durable Transgene Expression"],"prefix":"10.1021","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2669-6241","authenticated-orcid":true,"given":"Qing","family":"Sun","sequence":"first","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaole","family":"Cui","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Li","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Vervaeke","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Lienenklaus","sequence":"additional","affiliation":[{"name":"Hannover Medical School , , Carl-Neuberg-Str. 1 , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriane","family":"Gillon","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]},{"name":"Ghent University , , ,","place":["Ghent, Belgium, 9000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"De Sutter","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Helsmoortel","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"Devriendt","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne","family":"Snoeck","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4585-0343","authenticated-orcid":true,"given":"Niek N.","family":"Sanders","sequence":"additional","affiliation":[{"name":"Ghent University , , ,","place":["Merelbeke, Belgium, B-9820"]},{"name":"Ghent University , , ,","place":["Ghent, Belgium, 9000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"issue":"1\u20133","key":"2026080409265732900_cit1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jbiotec.2004.06.007","article-title":"Challenges and Solutions\nfor the Delivery of Biotech\nDrugs\u2013a Review of Drug Nanocrystal Technology and Lipid Nanoparticles","volume":"113","author":"Muller","year":"2004","journal-title":"J. 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