Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr;34(14):e2107506.
doi: 10.1002/adma.202107506. Epub 2022 Mar 1.

Inhaled mRNA Nanoformulation with Biogenic Ribosomal Protein Reverses Established Pulmonary Fibrosis in a Bleomycin-Induced Murine Model

Rui Zhang  1 , Weiqiang Jing  2 , Chen Chen  1 , Shengchang Zhang  1 , Mohnad Abdalla  1 , Peng Sun  3 , Ganyu Wang  2 , Wenjie You  4 , Zhenmei Yang  1 , Jing Zhang  1 , Chunwei Tang  1 , Wei Du  1 , Ying Liu  1 , Xiaoxun Li  1 , Jitian Liu  1 , Xiaona You  1 , Huili Hu  5 , Lei Cai  6 , Fengbo Xu  7 , Baixiang Dong  7 , Minglu Liu  8 , Bangming Qiang  8 , Yanhua Sun  9 , Gongchang Yu  10 , Jibiao Wu  3 , Kun Zhao  1 , Xinyi Jiang  1
Affiliations

Inhaled mRNA Nanoformulation with Biogenic Ribosomal Protein Reverses Established Pulmonary Fibrosis in a Bleomycin-Induced Murine Model

Rui Zhang et al. Adv Mater. 2022 Apr.

Abstract

Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to repetitive microinjuries to alveolar epithelial cells (AECs) and progresses with an overwhelming deposition of extracellular matrix (ECM), ultimately resulting in fibrotic scars and destroyed the alveolar architecture. Here, an inhaled ribosomal protein-based mRNA nanoformulation is reported for clearing the intrapulmonary ECM and re-epithelializing the disrupted alveolar epithelium, thereby reversing established fibrotic foci in IPF. The nanoformulation is sequentially assembled by a ribosomal protein-condensed mRNA core, a bifunctional peptide-modified corona and keratinocyte growth factor (KGF) with a PEGylated shielding shell. When inhaled via a nebulizer, the nanoformulations carried by microdrops are deposited in the alveoli, and penetrate into fibrotic foci, where the outer KGFs are detached after matrix metalloproteinase 2 (MMP2) triggering. The RGD motif-grafted cores then expose and specifically target the integrin-elevated cells for the intracellular delivery of mRNA. Notably, repeated inhalation of the nanoformulations accelerates the clearance of locoregional collagen by boosting the intralesional expression of MMP13 and alveolar re-epithelialization mediated by KGFs, which synergistically ameliorates the lung function of a bleomycin-induced murine model. Therefore, this work provides an alternative mRNA-inhalation delivery strategy, which shows great potential for the treatment of IPF.

Keywords: cationic ribosomal protein; idiopathic pulmonary fibrosis; inhalation; messenger RNA; reversing fibrotic foci.

PubMed Disclaimer

References

    1. a) S. Rangarajan, N. B. Bone, A. A. Zmijewska, S. Jiang, D. W. Park, K. Bernard, M. L. Locy, S. Ravi, J. Deshane, R. B. Mannon, E. Abraham, V. Darley-Usmar, V. J. Thannickal, J. W. Zmijewski, Nat. Med. 2018, 24, 1121;
    1. b) L. Richeldi, H. R. Collard, M. G. Jones, Lancet 2017, 389, 1941.
    1. a) T. E. King, A. Pardo, M. Selman, Lancet 2011, 378, 1949;
    1. b) F. J. Martinez, H. R. Collard, A. Pardo, G. Raghu, L. Richeldi, M. Selman, J. J. Swigris, H. Taniguchi, A. U. Wells, Nat. Rev. Dis. Primers 2017, 3, 17074.
    1. a) D. L. Clarke, L. A. Murray, B. Crestani, M. A. Sleeman, Pharmacol. Ther. 2017, 169, 35;

MeSH terms