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
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (66)
CITATIONS (8)