Recruiting T-cells toward the brain for enhanced glioblastoma chemo-immunotherapy efficacy by co-delivery of cytokines and temozolomide via ultrasound-gated redox-responsive extracellular vesicles

  • J Nanobiotechnology. 2025 Dec 7;23(1):766. doi: 10.1186/s12951-025-03885-y.
Lei Dong  #  1  2  3 ,  Qing Xu  #  2 ,  Hanjiao Liu  #  4 ,  Ran Li  3 ,  Zhengcheng Yun  1 ,  Huijie Yang  5 ,  Ziyan Gu  1 ,  Junfan Wei  6 ,  Haochun Guo  1 ,  Zhanhai Wei  1 ,  Haijun Zhang  7
Affiliations
  • 1. Department of Oncology, Medical School, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China.
  • 2. Department of Radiology, Peking University Shenzhen Hospital, Shenzhen, 518036, China.
  • 3. Department of Ultrasound, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453199, China.
  • 4. Department of Nursing, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China.
  • 5. Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P.R. China.
  • 6. Department of Nursing, Nanjing Central Hospital, 116 Chengxian Street, Nanjing, 210000, China.
  • 7. Department of Oncology, Medical School, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China. [email protected].
  • # Contributed equally.
PMID: 41354801 DOI: 10.1186/s12951-025-03885-y
Abstract

The main limitation of chemo-immunotherapy in glioblastoma (GBM) is the immunosuppressive tumor microenvironment (TME) and the restricted permeability of the blood-brain barrier (BBB). Here, we engineer redox-responsive macrophage-derived extracellular vesicles (M-EVs)-based nanovesicles (TC@MEVs) co-loaded with chemokine CXC chemokine ligand 10 (CXCL10) and temozolomide (TMZ). Combined with ultrasound (US)-mediated BBB opening, TC@MEVs release CXCL10 to recruit CD8+ T cells to the GBM region, synergizing with the high concentration of TMZ to amplify the chemo-immunotherapy efficacy of GBM. Consequently, up to 5.52-fold increase in CD8+ T cells are observed with US-guided co-delivery of CXCL10 and TMZ, compared to free TMZ and CXCL10. This spatiotemporal combination strategy enhances chemo-immunotherapy by reducing Tregs by 46%, increasing the M1/M2 macrophage ratio by 10.05-fold, achieving 40% tumor elimination, prolonging survival, and establishing long-term immune memory in orthotopic GBM mice. Overall, US-mediated the redox-responsive M-EVs nanovesicles to reverse the immunosuppressive TME by improving the infiltration of CD8+ T cells and local release of TMZ, may present a promising strategy for effective GBM chemo-immunotherapy.

Keywords
CD8+T cells; Chemo-immunotherapy; Extracellular vesicles; Glioblastoma; Tumor microenvironment.
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