{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T06:06:51Z","timestamp":1784268411131,"version":"3.55.0"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zangi lab Seed fund","award":["2856825"],"award-info":[{"award-number":["2856825"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Pulmonary fibrosis is a progressive and fatal disease characterized by excessive extracellular matrix deposition and irreversible lung remodeling. Although modified mRNA (modRNA) therapeutics offer a promising strategy for regulating disease-driving pathways, effective pulmonary delivery remains challenging due to the inherent liver tropism of conventional lipid nanoparticles (LNPs). This study aimed to establish an optimized platform for lung-selective modRNA delivery and therapeutic screening for pulmonary fibrosis. Methods: A panel of charge-modified LNP formulations was evaluated in vivo for pulmonary tropism following systemic administration of luciferase (Luc) modRNA. Administration routes, biodistribution in healthy and bleomycin (BLM)-induced fibrotic lungs, and endogenous microRNA (miRNA)-mediated de-targeting strategies were assessed. Candidate antifibrotic modRNAs targeting the transforming growth factor-beta (TGF-\u03b2) signaling pathway were subsequently evaluated in normal human lung fibroblasts (NHLFs). Results: Among the formulations tested, 50% DOTAP MC3 LNPs demonstrated the most favorable balance of pulmonary transfection, physicochemical properties, and limited off-target expression. Intravenous (IV) administration achieved robust lung expression with a superior safety profile compared with intratracheal (IT) delivery. Importantly, pulmonary biodistribution was preserved in BLM-induced fibrotic lungs despite extensive tissue remodeling. Incorporation of miR-122 recognition sites further enhanced selectivity, resulting in 94.5% of total transgene expression being localized to the lungs while substantially reducing residual hepatic expression. In vitro screening identified dominant-negative TGF-\u03b2 receptor II (DNTGFBR2) modRNA as a potent inhibitor of TGF-\u03b2-induced fibrotic activation, significantly suppressing \u03b1-SMA and CTGF expression. Conclusions: These findings establish a comprehensive platform for pulmonary modRNA therapeutic development by integrating lung-selective LNP engineering, optimal systemic delivery, miRNA-mediated de-targeting, and therapeutic payload screening. This strategy provides a foundation for the development of targeted RNA therapies for pulmonary fibrosis and other organ-specific diseases.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070868","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:32:17Z","timestamp":1784266337000},"page":"868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimization of Therapeutic modRNA Delivery to the Lung for Prevention of Pulmonary Fibrosis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5931-5035","authenticated-orcid":false,"given":"Gayatri","family":"Mainkar","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8625-7274","authenticated-orcid":false,"given":"Magdalena M.","family":"Zak","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2191-6942","authenticated-orcid":false,"given":"Matteo","family":"Ghiringhelli","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimeen","family":"Yoo","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Adjmi","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerat","family":"Kaur","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lior","family":"Zangi","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17074","DOI":"10.1038\/nrdp.2017.74","article-title":"Idiopathic pulmonary fibrosis","volume":"3","author":"Martinez","year":"2017","journal-title":"Nat. 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