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

  • J Extracell Vesicles. 2024 Dec;13(12):e70025. doi: 10.1002/jev2.70025.
Bei Zhang  1  2 ,  Jianqiang Chen  1 ,  Jiming Chen  3  4  5 ,  Yingying Shen  6 ,  Yinghu Chen  7 ,  Shibo Wang  1 ,  Chengyan Zhang  8 ,  Yuzhou He  9 ,  Huajun Feng  10 ,  Jiaoli Wang  11 ,  Zhijian Cai  1
Affiliations
  • 1. Department of Orthopaedics of the Second Affiliated Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3. Key Laboratory of Functional and Clinical Translational Medicine, Fujian province university, Xiamen Medical College, Xiamen, China.
  • 4. Institute of Respiratory Diseases Xiamen Medical College, Xiamen, China.
  • 5. Organiod platform of medical laboratory science, Xiamen medical college, Xiamen, China.
  • 6. Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
  • 7. Department of Infectious Disease, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China.
  • 8. Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 9. Department of Emergency, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
  • 10. Ecological-Environment & Health College, Zhejiang A & F University, Hangzhou, Zhejiang, China.
  • 11. Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
PMID: 39676736 DOI: 10.1002/jev2.70025
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.

Keywords
Bcl2 siRNA; T‐cell malignancies; anti‐CD7 single‐chain variable fragment; cytochrome C; extracellular vesicles.
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