{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:36:30Z","timestamp":1792787790733,"version":"4.5.0"},"reference-count":38,"publisher":"European Respiratory Society (ERS)","issue":"3","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Beijing Natural Science Foundation Joint Research Program for Basic Science Cooperation in the Beijing-Tianjin-Hebei Region","award":["J230030"],"award-info":[{"award-number":["J230030"]}]},{"name":"Beijing Natural Science Foundation Joint Research Program for Basic Science Cooperation in the Beijing-Tianjin-Hebei Region","award":["JQ23029"],"award-info":[{"award-number":["JQ23029"]}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC3401100"],"award-info":[{"award-number":["2022YFC3401100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32550198"],"award-info":[{"award-number":["32550198"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82090014"],"award-info":[{"award-number":["82090014"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370514"],"award-info":[{"award-number":["82370514"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82522010"],"award-info":[{"award-number":["82522010"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82570058"],"award-info":[{"award-number":["82570058"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92468105"],"award-info":[{"award-number":["92468105"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["W2421096"],"award-info":[{"award-number":["W2421096"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2023ZD0506903"],"award-info":[{"award-number":["2023ZD0506903"]}]},{"name":"Peking University Medicine plus X Pilot Program-Platform Construction Project","award":["2024YXXLHPT009"],"award-info":[{"award-number":["2024YXXLHPT009"]}],"id":[{"id":"https:\/\/ror.org\/02v51f717","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2026,4,14]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Emphysema, a major component of COPD characterised by progressive alveolar destruction, lacks effective medical therapies. Hepatocyte growth factor (HGF) possesses potent regenerative functions, but its therapeutic potential remains unrealised due to challenges in achieving targeted delivery and sustained lung expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We first assessed associations between HGF expression and emphysema severity using human datasets, lung tissue, and both elastase-induced and cigarette-smoke-induced murine models. We repurposed a clinical-stage SM102 lipid nanoparticles platform to deliver human HGF mRNA in murine models, evaluating therapeutic efficacy\n                      <jats:italic>via<\/jats:italic>\n                      intratracheal instillation in the elastase model. After optimising nebulisation, we assessed efficacy in the cigarette-smoke model. We investigated underlying mechanisms\n                      <jats:italic>via<\/jats:italic>\n                      single-cell RNA sequencing (scRNA-seq), which we validated in patient-derived lung organoids.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HGF expression displayed a biphasic pattern across the emphysema spectrum, with upregulation in milder disease states and marked reduction in advanced emphysema. Intratracheal delivery of HGF mRNA lipid nanoparticles restored lung function and attenuated alveolar destruction in the elastase model. Nebulised delivery achieved efficient pulmonary distribution and demonstrated comparable therapeutic efficacy in the cigarette-smoke model, including improved lung function, reduced inflammation, and decreased apoptosis. scRNA-seq analysis detected enhanced alveolar type II (AT2) cell proliferation and differentiation in the elastase model and human organoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study provides proof-of-concept evidence for a therapeutic strategy for emphysema. Using a clinical-stage lipid nanoparticle platform, we demonstrate that HGF mRNA therapy is effective\n                      <jats:italic>via<\/jats:italic>\n                      both direct instillation and optimised nebulisation, prompting structural and functional recovery by activating endogenous repair pathways in AT2 cells.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.02323-2025","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T15:35:16Z","timestamp":1777649716000},"page":"2502323","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Lung-targeted hepatocyte growth factor mRNA restores alveolar structure in experimental emphysema"],"prefix":"10.1183","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1962-7850","authenticated-orcid":false,"given":"Dian","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijing","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanhe","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixia","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongxinwei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7424-3492","authenticated-orcid":false,"given":"Huanyu","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyang","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-4411","authenticated-orcid":false,"given":"Simin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5375-2993","authenticated-orcid":false,"given":"Rongbing","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangliang","family":"Qiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aihong","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-0147","authenticated-orcid":false,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"2026100511101124000_68.3.2502323.1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200912-1843CC"},{"key":"2026100511101124000_68.3.2502323.2","unstructured":"Global Initiative for Chronic Obstructive Lung Disease . Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2025 Report). https:\/\/goldcopd.org\/2025-gold-report\/"},{"key":"2026100511101124000_68.3.2502323.3","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.pccm.2023.03.004","article-title":"Twenty years of changes in the definition of early chronic obstructive pulmonary disease","volume":"1","author":"Chen","year":"2023","journal-title":"Chin Med J Pulm Crit Care Med"},{"key":"2026100511101124000_68.3.2502323.4","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S2213-2600(16)30221-1","article-title":"Lung volume reduction for emphysema","volume":"5","author":"Shah","year":"2017","journal-title":"Lancet Respir Med"},{"key":"2026100511101124000_68.3.2502323.5","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201007-1091OC"},{"key":"2026100511101124000_68.3.2502323.6","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S175830"},{"key":"2026100511101124000_68.3.2502323.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-59641-1"},{"key":"2026100511101124000_68.3.2502323.8","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1038\/s41467-025-57163-4","article-title":"Heparan sulfate regulates myofibroblast heterogeneity and function to mediate niche homeostasis during alveolar morphogenesis","volume":"16","author":"He","year":"2025","journal-title":"Nat Commun"},{"key":"2026100511101124000_68.3.2502323.9","doi-asserted-by":"crossref","first-page":"e1003228","DOI":"10.1371\/journal.pgen.1003228","article-title":"Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung","volume":"9","author":"Calvi","year":"2013","journal-title":"PLoS Genet"},{"key":"2026100511101124000_68.3.2502323.10","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200504-567OC"},{"key":"2026100511101124000_68.3.2502323.11","doi-asserted-by":"publisher","DOI":"10.1007\/s10157-015-1211-2"},{"key":"2026100511101124000_68.3.2502323.12","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1042\/CS20150502","article-title":"Cellular and molecular mechanisms of HGF\/Met in the cardiovascular system","volume":"129","author":"Gallo","year":"2015","journal-title":"Clin Sci"},{"key":"2026100511101124000_68.3.2502323.13","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200603-406OC"},{"key":"2026100511101124000_68.3.2502323.14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2006.01522.x"},{"key":"2026100511101124000_68.3.2502323.15","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000158433.89103.85"},{"key":"2026100511101124000_68.3.2502323.16","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200411-1518OC"},{"key":"2026100511101124000_68.3.2502323.17","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/s41578-021-00358-0","article-title":"Lipid nanoparticles for mRNA delivery","volume":"6","author":"Hou","year":"2021","journal-title":"Nat Rev Mater"},{"key":"2026100511101124000_68.3.2502323.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-01042-y"},{"key":"2026100511101124000_68.3.2502323.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-020-0669-6"},{"key":"2026100511101124000_68.3.2502323.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2116271119"},{"key":"2026100511101124000_68.3.2502323.21","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.jconrel.2022.03.032","article-title":"mRNA vaccines for COVID-19 and diverse diseases","volume":"345","author":"Hussain","year":"2022","journal-title":"J Control Release"},{"key":"2026100511101124000_68.3.2502323.22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035389"},{"key":"2026100511101124000_68.3.2502323.23","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00166.2005"},{"key":"2026100511101124000_68.3.2502323.24","doi-asserted-by":"crossref","first-page":"719","DOI":"10.2147\/COPD.S3078","article-title":"Pulmonary and systemic hepatocyte and keratinocyte growth factors in patients with chronic obstructive pulmonary disease","volume":"3","author":"Sauleda","year":"2008","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"2026100511101124000_68.3.2502323.25","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.06.00120604"},{"key":"2026100511101124000_68.3.2502323.26","doi-asserted-by":"publisher","DOI":"10.1002\/path.1748"},{"key":"2026100511101124000_68.3.2502323.27","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01606-2022"},{"key":"2026100511101124000_68.3.2502323.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.03.010"},{"key":"2026100511101124000_68.3.2502323.29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68782"},{"key":"2026100511101124000_68.3.2502323.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam6603"},{"key":"2026100511101124000_68.3.2502323.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2022.09.129"},{"key":"2026100511101124000_68.3.2502323.32","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s10456-024-09967-z","article-title":"A novel quantitative angiogenesis assay based on visualized vascular organoid","volume":"28","author":"Zhao","year":"2025","journal-title":"Angiogenesis"},{"key":"2026100511101124000_68.3.2502323.33","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1016\/j.stem.2025.05.014","article-title":"Rapid generation of functional vascular organoids via simultaneous transcription factor activation of endothelial and mural lineages","volume":"32","author":"Gong","year":"2025","journal-title":"Cell Stem Cell"},{"key":"2026100511101124000_68.3.2502323.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-021-00439-4"},{"key":"2026100511101124000_68.3.2502323.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50093-7"},{"key":"2026100511101124000_68.3.2502323.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2622-0"},{"key":"2026100511101124000_68.3.2502323.37","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.3390\/vaccines9091007","article-title":"Development of an mRNA-LNP vaccine against SARS-CoV-2: evaluation of immune response in mouse and rhesus macaque","volume":"9","author":"Naderi Sohi","year":"2021","journal-title":"Vaccines"},{"key":"2026100511101124000_68.3.2502323.38","doi-asserted-by":"crossref","first-page":"6477","DOI":"10.1038\/s41467-025-61688-z","article-title":"Boosting RNA nanotherapeutics with V-ATPase activating non-inflammatory lipid nanoparticles to treat chronic lung injury","volume":"16","author":"Zhao","year":"2025","journal-title":"Nat Commun"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.02323-2025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:10:21Z","timestamp":1791223821000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.02323-2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":38,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9,25]]},"published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1183\/13993003.02323-2025"],"URL":"https:\/\/doi.org\/10.1183\/13993003.02323-2025","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]}}}