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; Pulmonary Fibrosis; Lipids; Idiopathic Pulmonary Fibrosis; Pulmonary Alveoli; Mice; Mucus; Bleomycin; Disease Models, Animal; 03 medical and health sciences; 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 idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids high-efficiency mucus penetration codelivery messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, reverses mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits accelerated senescence cells. Concurrently, pathological remodeling fibroblast activation induced by are terminated, ultimately prompting regeneration. Our data demonstrated that mRNA-LNP system exhibited high expression lung cells, markedly extricated collapse prolonged survival mice, providing clinically viable strategy against IPF.