Endothelium‐Derived Engineered Extracellular Vesicles Protect the Pulmonary Endothelial Barrier in Acute Lung Injury

Author:

Gu Zhengyan12ORCID,Sun Mingxue1,Liu Jihao1,Huang Qi3,Wang Yunqin1,Liao Jun24,Shu Tingbin1,Tao Min1,Mao Guanchao1,Pei Zhipeng1,Meng Wenqi1,Zhang Xinkang1,Wei Youheng5,Zhang Shanshan1,Li Songling1,Xiao Kai16ORCID,Lu Ying2ORCID,Xu Qingqiang17ORCID

Affiliation:

1. Lab of Toxicology and Pharmacology Faculty of Naval Medicine Naval Medical University Shanghai 200433 P. R. China

2. Department of Pharmaceutical Sciences School of Pharmacy Naval Medical University Shanghai 200433 P. R. China

3. School of Traditional Chinese Materia Medica Shenyang Pharmaceutical University Shenyang 110006 P. R. China

4. School of Medicine Shanghai University Shanghai 200444 P. R. China

5. State Key Laboratory of Genetic Engineering Institute of Genetics Fudan University Shanghai 200433 P. R. China

6. Marine Biomedical Science and Technology Innovation Platform of Lingang Special Area Shanghai 200433 P. R. China

7. Basic Medical Center for Pulmonary Disease Faculty of Naval Medicine Naval Medical University Shanghai 200433 P. R. China

Abstract

AbstractAcute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium‐derived engineered extracellular vesicles (eEVs) that deliver microRNA‐125b‐5p (miRNA‐125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell‐targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA‐125b is loaded into EVs. Finally, LET‐EVs‐miRNA‐125b is constructed. The results show that compared to the EVs, miRNA‐125b, and EVs‐miRNA‐125b, LET‐EVs‐miRNA‐125b exhibit the most significant treatment efficacy in ALI. Moreover, LET‐EVs‐miRNA‐125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET‐EVs‐miRNA‐125b downregulates early growth response‐1 (EGR1) levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET‐EVs‐miRNA‐125b can treat ALI by protecting the endothelial barrier integrity.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Shanghai

National Key Research and Development Program of China

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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