Boosting RNA nanotherapeutics with V-ATPase activating non-inflammatory lipid nanoparticles to treat chronic lung injury
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.
Authors
- Shaokun Shu (ORCID: https://orcid.org/0000-0001-6839-2782)
- Cong Luo (ORCID: https://orcid.org/0000-0002-0506-9598)
- J. C. Chen
- Shuai Liu (ORCID: https://orcid.org/0000-0002-8405-6743)
- Xinzhu Shan
- Xueguang Lu (ORCID: https://orcid.org/0000-0002-1069-7265)
- Shengran Zhang
- Y Liu (ORCID: https://orcid.org/0000-0003-2979-6017)
- Xue Qiao (ORCID: https://orcid.org/0000-0002-8771-7877)
- Chenglin Song (ORCID: https://orcid.org/0000-0001-5926-9993)
- Fang Yang (ORCID: https://orcid.org/0000-0002-5829-5601)
- Xingdi Cheng
- Hongkun Wu (ORCID: https://orcid.org/0000-0002-9459-6583)
- Chenlong Wei
- Zefeng Wang (ORCID: https://orcid.org/0000-0002-6605-3637)
- Lei Miao (ORCID: https://orcid.org/0009-0004-1647-1445)
- Bin Ma (ORCID: https://orcid.org/0000-0002-3913-0545)
- Zhiqiang Zhao (ORCID: https://orcid.org/0000-0002-7615-6437)
- Wendi Huang (ORCID: https://orcid.org/0000-0003-3571-9288)
- Qingqing Yang (ORCID: https://orcid.org/0009-0002-0698-5499)
- Buyao Li
- Jing Ding
Institutions
- Shenyang Pharmaceutical University (CN)
- University of North Carolina at Chapel Hill (US)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Southern University of Science and Technology (CN)
- Peking University Cancer Hospital (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Beijing National Laboratory for Molecular Sciences (CN)
- Peking University People's Hospital (CN)
- Peking University International Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- First Affiliated Hospital Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-14
- DOI
- https://doi.org/10.1038/s41467-025-61688-z
- Citations
- 10
- Primary Topic
- ATP Synthase and ATPases Research
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Beijing Municipality
- Beijing Municipal Science and Technology Commission