{"title":"CD7-targeting pro-apoptotic extracellular vesicles: A novel approach for T-cell haematological malignancy therapy","authors":"Bei Zhang, Jianqiang Chen, Jiming Chen, Yingying Shen, Yinghu Chen, Shibo Wang, Chengyan Zhang, Yuzhou He, Huajun Feng, Jiaoli Wang, Zhijian Cai","doi":"10.1002/jev2.70025","DOIUrl":null,"url":null,"abstract":"<p>T-cell haematological malignancies progress rapidly and have a high mortality rate and effective treatments are still lacking. Here, we developed a drug delivery system utilizing 293T cell-derived extracellular vesicles (EVs) modified with an anti-CD7 single-chain variable fragment (αCD7/EVs). Given the challenges of chemotherapy resistance in patients with T-cell malignancy, we selected cytochrome C (CytC) and <i>Bcl2</i> siRNA (<i>siBcl2</i>) as therapeutic agents and loaded them into αCD7/EVs (αCD7/EVs/CytC/<i>siBcl2</i>). We found that αCD7/EVs efficiently targeted and were internalized by human T-ALL Molt-4 cells. In addition, the interaction between αCD7 and CD7 switched the EV entry pathway in Molt-4 cells from macropinocytosis-dependent endocytosis to clathrin-mediated endocytosis, thereby reducing EV-lysosome colocalization, ultimately improving CytC delivery efficiency and increasing the cytotoxicity of nascent EVs from EV-treated Molt-4 cells. Notably, αCD7/EVs/CytC/<i>siBcl2</i> demonstrated similar efficacy against both Molt-4 and chemotherapy-resistant Molt-4 cells (CR-Molt-4). Furthermore, αCD7/EVs/CytC/<i>siBcl2</i> exhibited high safety, low immunogenicity and minimal impact on human T cells. Therefore, αCD7/EVs/CytC/<i>siBcl2</i> are promising therapeutic approaches for treating CD7<sup>+</sup> T-cell malignancies.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"13 12","pages":""},"PeriodicalIF":15.5000,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70025","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Extracellular Vesicles","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jev2.70025","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
CD7-targeting pro-apoptotic extracellular vesicles: A novel approach for T-cell haematological malignancy therapy
T-cell haematological malignancies progress rapidly and have a high mortality rate and effective treatments are still lacking. Here, we developed a drug delivery system utilizing 293T cell-derived extracellular vesicles (EVs) modified with an anti-CD7 single-chain variable fragment (αCD7/EVs). Given the challenges of chemotherapy resistance in patients with T-cell malignancy, we selected cytochrome C (CytC) and Bcl2 siRNA (siBcl2) as therapeutic agents and loaded them into αCD7/EVs (αCD7/EVs/CytC/siBcl2). We found that αCD7/EVs efficiently targeted and were internalized by human T-ALL Molt-4 cells. In addition, the interaction between αCD7 and CD7 switched the EV entry pathway in Molt-4 cells from macropinocytosis-dependent endocytosis to clathrin-mediated endocytosis, thereby reducing EV-lysosome colocalization, ultimately improving CytC delivery efficiency and increasing the cytotoxicity of nascent EVs from EV-treated Molt-4 cells. Notably, αCD7/EVs/CytC/siBcl2 demonstrated similar efficacy against both Molt-4 and chemotherapy-resistant Molt-4 cells (CR-Molt-4). Furthermore, αCD7/EVs/CytC/siBcl2 exhibited high safety, low immunogenicity and minimal impact on human T cells. Therefore, αCD7/EVs/CytC/siBcl2 are promising therapeutic approaches for treating CD7+ T-cell malignancies.
期刊介绍:
The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies.
The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.