2. Academic Validation
  3. Boosting RNA nanotherapeutics with V-ATPase activating non-inflammatory lipid nanoparticles to treat chronic lung injury

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

  • Nat Commun. 2025 Jul 14;16(1):6477. doi: 10.1038/s41467-025-61688-z.
Zhiqiang Zhao # 1 2 3,  Xinzhu Shan # 1 2,  Jing Ding # 4,  Bin Ma # 1 2,  Buyao Li 1 2,  Wendi Huang 5,  Qingqing Yang 6 7 8 9,  Yian Fang 1 2,  Junhe Chen 10,  Chenglin Song 1,  Chenlong Wei 1 2,  Shuai Liu 11,  Xingdi Cheng 11 12,  Shengran Zhang 1 2,  Yunxuan Liu 1 2,  Hongkun Wu 13,  Cong Luo 3,  Shaokun Shu 6 7 8 9,  Xue Qiao 1,  Zefeng Wang 14 15,  Xueguang Lu 16 17,  Lei Miao 18 19 20
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 2 Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 3 Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, China.
  • 4 Department of Pediatrics, Peking University People's Hospital, Beijing, PR China. dingjingvv@126.com.
  • 5 Shanghai Institute for Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 6 Peking University International Cancer Institute, Beijing, China.
  • 7 State Key Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
  • 8 Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China.
  • 9 Peking University-Yunnan Baiyao International Medical Research Center, Beijing, China.
  • 10 University of North Carolina at Chapel Hill, North Carolina, USA.
  • 11 Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
  • 12 University of Chinese Academy of Sciences, Beijing, China.
  • 13 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 14 Shanghai Institute for Nutrition and Health, Chinese Academy of Sciences, Shanghai, China. wangzf@sustech.edu.cn.
  • 15 School of Life Science, Southern University of Science and Technology, Shenzhen, China. wangzf@sustech.edu.cn.
  • 16 Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China. xueguang@iccas.ac.cn.
  • 17 University of Chinese Academy of Sciences, Beijing, China. xueguang@iccas.ac.cn.
  • 18 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. lmiao_pharm@bjmu.edu.cn.
  • 19 Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China. lmiao_pharm@bjmu.edu.cn.
  • 20 Peking University-Yunnan Baiyao International Medical Research Center, Beijing, China. lmiao_pharm@bjmu.edu.cn.
  • # Contributed equally.
PMID: 40659631 DOI: 10.1038/s41467-025-61688-z
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.

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