Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice

• DOI: 10.1126/sciadv.ado4791
• Publication Date: 2024-06-12T17:58:25Z
• Authors: Yan Wang; Jing Zhang; Ying Liu; Xiao Yue; Kun Han; Zhichao Kong; Yuanmin Dong; Zhenmei Yang; Zhipeng Fu; Chunwei Tang; Chongdeng Shi; Xiaotian Zhao; Maosen Han; Zhibin Wang; Yulin Zhang; Chen Chen; Anning Li; Peng Sun; Danqing Zhu; Kun Zhao; Xinyi Jiang
• Keywords: 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

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.