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Beck, C.* ; Ramanujam, D.* ; Vaccarello, P.* ; Widenmeyer, F.* ; Feuerherd, M. ; Cheng, C.C.* ; Bomhard, A.* ; Abikeeva, T.* ; Schädler, J.* ; Sperhake, J.P.* ; Graw, M.* ; Safi, S.* ; Hoffmann, H.* ; Staab-Weijnitz, C.A. ; Rad, R.* ; Protzer, U. ; Frischmuth, T.* ; Engelhardt, S.*

Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage.

Nat. Commun. 14:4564 (2023)

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Recent studies of severe acute inflammatory lung disease including COVID-19 identify macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 is among the strongest upregulated microRNAs in human COVID-19 and in mice with acute inflammatory lung damage, and it is the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of a microRNA-21 inhibitor to trimannose achieves rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reverses pathological activation of macrophages and prevents pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevents the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Genes

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 14, Issue: 1, Article Number: 4564

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Virology (VIRO)
Institute of Lung Health and Immunity (LHI)

Grants DFG
European Union
BMBF
Bayerische Forschungsstiftung through CoVmiR
Deutsche Forschungsgemeinschaft (DFG)
German Federal Ministry of Education and Research BMBF
Freiburg Galaxy Team: Bjoern Gruening, Bioinformatics, University of Freiburg (Germany) - Collaborative Research Centre 992 Medical Epigenetics (DFG)