| 論文作者 |
Zhao, ZQ; Shan, XZ; Ding, J; Ma, B; Li, BY; Huang, WD; Yang, QQ; Fang, Y; Chen, JH; Song, CL; Wei, CL; Liu, S; Cheng, XD; Zhang, SR; Liu, YX; Wu, HK; Luo, C; Shu, SK; Qiao, X; Wang, ZF; Lu, XG; Miao, L |
| 摘要 |
Lipid nanoparticles (LNPs) are a promising platform for mRNA delivery. However, their use in inflammatory pulmonary diseases is limited by reactogenicity and suboptimal delivery. Here we develop a non-inflammatory LNP (NIF-LNP) by incorporating ursolic acid, identified from a natural product library, into a biodegradable, cationic phosphoramide-derived LNP formulation. NIF-LNPs exhibit a 40-fold enhancement in lung protein expression without causing significant reactogenicity compared to LNPs containing ALC-0315. Our CRISPR-KO mechanistic studies uncover that ursolic acid promote endosome acidification by activating the V-ATPase complex, acting as a central hub for endosomal trafficking of LNPs and inflammation control. Furthermore, we identify an intracellular circadian regulatory gene, NR1D1, encapsulated in NIF-LNPs, showing notable therapeutic efficacy in bronchopulmonary dysplasia and lung fibrosis. To enhance clinical feasibility, we have developed a lyophilized formulation that maintains stability for over 90 days and ensures efficient nebulization in preclinical male mouse, pup rat, and male dog models. Overall, this V-ATPase-activating atomized NIF-LNP presents a viable strategy for treating variable chronic inflammatory lung diseases. |
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