Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice
0301 basic medicine
0303 health sciences
Pulmonary Fibrosis
Lipids
Idiopathic Pulmonary Fibrosis
Pulmonary Alveoli
Mice
Mucus
Bleomycin
Disease Models, Animal
Alveolar Epithelial Cells
Administration, Inhalation
Liposomes
Animals
Nanoparticles
Humans
Biomedicine and Life Sciences
RNA, Messenger
DOI:
10.1126/sciadv.ado4791
Publication Date:
2024-06-12T17:58:25Z
AUTHORS (21)
ABSTRACT
The stemness loss–associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house–made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.
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