Chengkang Jin,1,* Yingjie Zhang,2,* Lin Chen,3,4,* Bingqing Chen,5,* Changjiang Chen,1 Hairui Zhang,1 Junping Guo,6,* Wei Chen,7,* Yi Shi,7 Chengping Wen1 

1College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 2College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310014, People’s Republic of China; 3School of Life sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 4Biological Macromolecules Development Department, Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd, Hangzhou, 310011, People’s Republic of China; 5Yue Yang Hospital of Traditional Chinese & Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China; 6Rainbowfish Rehabilitation and Nursing School, Hangzhou Vocational & Technical College, Hangzhou, 310018, People’s Republic of China; 7Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Chengping Wen, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China, Email wengcp@163.com Yi Shi, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 725 South WanPing Road, Shanghai, 200032, People’s Republic of China, Tel +86 021 64385700 3522, Email lh2918@shutcm.edu.cn

Introduction: Acute lung injury (ALI) seriously threatens human health and is induced by multiple factors. When ALI occurs, lung lesions affect gas exchange and may trigger respiratory failure. Current clinical treatments are limited, and traditional drug delivery has drawbacks. Berberine, a natural drug with anti-inflammatory effects, has difficulty in effectively exerting its efficacy.
Methods: The study designed a nano-micelle. Hydrophobic berberine was encapsulated with diselenide bonds as the linker. Then, lung epithelial cell membranes were extracted to encapsulate and disguise the nano-micelle. These nanoparticles were injected intravenously. Thanks to the cell membrane’s specificity, they could bind to lung tissue, achieving targeted lung delivery. In the inflamed area of acute lung injury, the significantly increased reactive oxygen species level was used to break the diselenide bonds, enabling precise berberine release at the lung injury site.
Results: The nano-drug (MM-NPs) was successfully prepared, with the encapsulation efficiency of berberine in the micelles reaching 68.2%. In a ROS environment, the nano-micelles could quickly release over 80% of berberine. In inflammatory MLE-12 cells, MM-NPs responded well to ROS, and cellular inflammatory factor levels were significantly improved after treatment. In a lipopolysaccharide (LPS)-induced pneumonia mouse model, MM-NPs achieved lung targeting. Further studies showed that MM-NPs administration significantly alleviated LPS-induced lung injury in mice. Additionally, evaluation indicated MM-NPs had good in-vivo safety with no obvious adverse reactions.
Conclusion: This study successfully developed a novel delivery system, MM-NPs, overcoming berberine’s low bioavailability problem in treating acute lung injury. The system has excellent physicochemical properties, biocompatibility, and metabolic safety. In vitro and animal experiments verified it can significantly enhance the therapeutic effect, offering new ideas and hopes for acute lung injury treatment. In the future, clinical trials can be advanced, and new lung targeting strategies explored for more therapeutic breakthroughs.

Keywords: acute lung injury, berberine, nano-micelles, lung-targeted delivery, reactive oxygen species