2. Academic Validation
  3. Engineered extracellular vesicles displaying bi-specific T-cell engagers for targeted therapy of B-cell malignancies

Engineered extracellular vesicles displaying bi-specific T-cell engagers for targeted therapy of B-cell malignancies

  • Exp Hematol Oncol. 2026 Feb 7;15(1):21. doi: 10.1186/s40164-026-00749-5.
Xiuxiu Yang # 1 2,  Qian Xu # 3 4,  Jue Wang # 3,  Shanwei Ye 1 2 3,  Caroline Markmann 4,  Shujia Zhang 1 2 3,  Qian Zhang 4,  Vijay G Bhoj 5,  Liang Huang 6 7,  Zheng Zhang 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.
  • 2 Tianjin Institutes of Health Science, Tianjin, 301600, China.
  • 3 Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technolog, Wuhan, 430030, Hubei, China.
  • 4 Department of Pathology & Laboratory Medicine, Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 5 Department of Pathology & Laboratory Medicine, Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • 6 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China. [email protected].
  • 7 Tianjin Institutes of Health Science, Tianjin, 301600, China. [email protected].
  • 8 Department of Pathology & Laboratory Medicine, Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
  • 9 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. [email protected].
  • # Contributed equally.
PMID: 41654887 DOI: 10.1186/s40164-026-00749-5
Abstract

Despite the clinical success of T cell-based immunotherapies such as CAR-T cells and bispecific T cell engagers (BiTEs), therapeutic resistance and immune suppression remain significant barriers in B-cell malignancies. To address these, we developed a novel dual-functional extracellular vesicle (EV) platform, termed BiTE EV@STA, that displays anti-CD3/CD19 BiTE molecules on the EV surface while encapsulating a STING agonist (STA). This strategy enables simultaneous redirection of cytotoxic T cells to tumor cells and stimulation of innate immunity within the tumor microenvironment (TME). BiTE EVs demonstrated favorable pharmacokinetics, enhanced tumor targeting, and robust T cell dependent cytotoxicity and cytokine release. In Nalm6-Luc xenograft models, BiTE EVs significantly inhibited tumor progression and prolonged survival. Further loading of STING agonists into EVs (BiTE EV@STA) activated dendritic cells, and enhanced CD8⁺ T cell infiltration in the TME. Notably, BiTE EV@STA achieved a 4-fold increase in tumor growth inhibition and a marked survival benefit compared to either component alone. This study presents BiTE EV@STA as a promising EV-based immunotherapy that integrates adaptive and innate immune activation to overcome TME-mediated resistance. These findings may have broad implications for enhancing T cell-based therapies in hematologic malignancies and beyond.

Keywords

B-cell malignancy; Bispecific T cell engager; Extracellular vesicle; Immunotherapy; Tumor microenvironment; cGAS-STING signaling pathway.

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