CD7-targeting pro-apoptotic extracellular vesicles: A novel approach for T-cell haematological malignancy therapy

IF 15.5 1区医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-12-16 DOI:10.1002/jev2.70025

Bei Zhang, Jianqiang Chen, Jiming Chen, Yingying Shen, Yinghu Chen, Shibo Wang, Chengyan Zhang, Yuzhou He, Huajun Feng, Jiaoli Wang, Zhijian Cai

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Abstract

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.

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T细胞血液恶性肿瘤进展迅速，死亡率高，但目前仍缺乏有效的治疗方法。在此，我们开发了一种药物递送系统，利用经抗 CD7 单链可变片段（αCD7/EVs）修饰的 293T 细胞衍生胞外囊泡（EVs）。鉴于T细胞恶性肿瘤患者面临化疗耐药性的挑战，我们选择细胞色素C（CytC）和Bcl2 siRNA（siBcl2）作为治疗药物，并将它们装入αCD7/EVs（αCD7/EVs/CytC/siBcl2）中。我们发现，αCD7/EVs 能有效靶向人 T-ALL Molt-4 细胞并被其内化。此外，αCD7和CD7之间的相互作用将Molt-4细胞中的EV进入途径从大蛋白依赖性内吞转变为凝集素介导的内吞，从而减少了EV与溶酶体的共定位，最终提高了CytC的递送效率，并增强了EV处理过的Molt-4细胞新生EV的细胞毒性。值得注意的是，αCD7/EVs/CytC/siBcl2 对 Molt-4 细胞和化疗耐药的 Molt-4 细胞（CR-Molt-4）具有相似的疗效。此外，αCD7/EVs/CytC/siBcl2 还具有安全性高、免疫原性低以及对人类 T 细胞影响最小等特点。因此，αCD7/EVs/CytC/siBcl2 是治疗 CD7+ T 细胞恶性肿瘤的有前途的治疗方法。

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来源期刊

Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

27.30

自引率

4.40%

发文量

115

审稿时长

12 weeks

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.