Boosting RNA nanotherapeutics with V-ATPase activating non-inflammatory lipid nanoparticles to treat chronic lung injury

Zhiqiang Zhao, Xinzhu Shan, Jing Ding (), Bin Ma, Buyao Li, Wendi Huang, Qingqing Yang, Yian Fang, Junhe Chen, Chenglin Song, Chenlong Wei, Shuai Liu, Xingdi Cheng, Shengran Zhang, Yunxuan Liu, Hongkun Wu, Cong Luo, Shaokun Shu, Xue Qiao, Zefeng Wang (), Xueguang Lu () and Lei Miao ()
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Zhiqiang Zhao: Peking University
Xinzhu Shan: Peking University
Jing Ding: Peking University People’s Hospital
Bin Ma: Peking University
Buyao Li: Peking University
Wendi Huang: Chinese Academy of Sciences
Qingqing Yang: Peking University International Cancer Institute
Yian Fang: Peking University
Junhe Chen: University of North Carolina at Chapel Hill
Chenglin Song: Peking University
Chenlong Wei: Peking University
Shuai Liu: Chinese Academy of Sciences
Xingdi Cheng: Chinese Academy of Sciences
Shengran Zhang: Peking University
Yunxuan Liu: Peking University
Hongkun Wu: the First Affiliated Hospital of Zhejiang University School of Medicine
Cong Luo: Shenyang Pharmaceutical University
Shaokun Shu: Peking University International Cancer Institute
Xue Qiao: Peking University
Zefeng Wang: Chinese Academy of Sciences
Xueguang Lu: Chinese Academy of Sciences
Lei Miao: Peking University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61688-z

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