Boosting RNA nanotherapeutics with V-ATPase activating non-inflammatory lipid nanoparticles to treat chronic lung injury PMID: 40659631

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
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. [email protected].
15. School of Life Science, Southern University of Science and Technology, Shenzhen, China. [email protected].
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. [email protected].
17. University of Chinese Academy of Sciences, Beijing, China. [email protected].
18. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. [email protected].
19. Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China. [email protected].
20. Peking University-Yunnan Baiyao International Medical Research Center, Beijing, China. [email protected].
# Contributed equally.

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.