Chen Wang, Xueying Zhou, Te Bu, Shuang Liang, Zhenzhen Hao, Mi Qu, Yang Liu, Mengying Wei, Changyang Xing, Guodong Yang, Lijun Yuan
{"title":"Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9.","authors":"Chen Wang, Xueying Zhou, Te Bu, Shuang Liang, Zhenzhen Hao, Mi Qu, Yang Liu, Mengying Wei, Changyang Xing, Guodong Yang, Lijun Yuan","doi":"10.1016/j.ymthe.2024.11.034","DOIUrl":null,"url":null,"abstract":"<p><p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the degradation of the low-density lipoprotein receptor (LDLR), and PCSK9 inhibition emerges as an attractive strategy for atherosclerosis management. In this study, extracellular vesicles (EVs) were engineered to nanosponges, which could efficiently adsorb and deliver PCSK9 into lysosomes for degradation. Briefly, nanosponges were engineered by modifying EVs with EGF-A/PTGFRN fusion protein (PCSK9 binding domain EGF-A from the mutant LDLR with higher affinity was fused to the C terminus of prostaglandin F2 receptor negative regulator). The modification endowed the EVs with hundreds of EGF-As displayed on the surface, and thus the capacity to adsorb PCSK9 efficiently. The adsorbed PCSK9 would thus be delivered into lysosomes for degradation when the nanosponges were endocytosed by liver cells, thus releasing endogenous LDLR from degradation. In the ApoE<sup>-/-</sup> mouse model, tail vein-injected nanosponges were able to degrade PCSK9, increase LDLR expression, lower the LDL-C level, and thus alleviate atherosclerosis. In summary, here we not only develop a novel strategy for PCSK9 inhibition but we also propose a universal method for adsorption and degradation of circulating proteins for disease management.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1000,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.11.034","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the degradation of the low-density lipoprotein receptor (LDLR), and PCSK9 inhibition emerges as an attractive strategy for atherosclerosis management. In this study, extracellular vesicles (EVs) were engineered to nanosponges, which could efficiently adsorb and deliver PCSK9 into lysosomes for degradation. Briefly, nanosponges were engineered by modifying EVs with EGF-A/PTGFRN fusion protein (PCSK9 binding domain EGF-A from the mutant LDLR with higher affinity was fused to the C terminus of prostaglandin F2 receptor negative regulator). The modification endowed the EVs with hundreds of EGF-As displayed on the surface, and thus the capacity to adsorb PCSK9 efficiently. The adsorbed PCSK9 would thus be delivered into lysosomes for degradation when the nanosponges were endocytosed by liver cells, thus releasing endogenous LDLR from degradation. In the ApoE-/- mouse model, tail vein-injected nanosponges were able to degrade PCSK9, increase LDLR expression, lower the LDL-C level, and thus alleviate atherosclerosis. In summary, here we not only develop a novel strategy for PCSK9 inhibition but we also propose a universal method for adsorption and degradation of circulating proteins for disease management.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.