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<p>Glioblastoma (GBM) immunotherapy is limited by the blood-brain barrier (BBB) and the tumor immune resistance. Here, we develop an engineered bacterial outer membrane vesicle (OMV) through safe and straightforward genetic modification of <i>Escherichia coli</i>, termed OMV-C-C, enabling co-expression of cell-penetrating peptides (CPP) and chlorotoxin (CLT) on its surface. The OMV-C-C efficiently crosses BBB and specifically targets tumor cells both in vitro and in vivo. A single intravenous administration of OMV-C-C significantly inhibit GBM growth by enhancing the infiltration of CD8<sup>+</sup> T cells in orthotopic brain tumor models. Mechanistically, interferon-gamma (IFN-γ) released by CD8<sup>+</sup> T cells induces ferroptosis-specific lipid peroxidation in tumor cells through inhibiting cystine-glutamate exchanger (system Xc<sup>−</sup>) and downregulating glutathione peroxidase 4 (GPX4), a pathway demonstrated to be extremely activated in human GBM samples. Furthermore, IFN-γ facilitates erastin- and RSL-3-induced ferroptosis of tumor cells, particularly in temozolomide (TMZ)-resistant cells. Additionally, OMV-C-C@RSL-3 synergistically suppresses GBM growth in vivo. Thus, biosynthetically engineered OMV-C-C integrates intrinsic immunomodulatory activity with ferroptosis enhancement to strengthen glioblastoma immunotherapies, offering a versatile platform to overcome limitations in brain tumor immunotherapy. </p> Graphical Abstract <p></p>

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Dual-targeted bacterial outer membrane vesicles enhance glioblastoma immunotherapy by regulating tumor microenvironment and inducing IFN-γ-mediated ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Chen Chen,
  • Xiaojing Zhu,
  • Zefeng Song,
  • Yutong Xing,
  • Wenrui Jin,
  • Fan Li,
  • Pir Tariq Shah,
  • Siqi Song,
  • Haoran Geng,
  • Kai Xu,
  • Hong Wang,
  • Zhenyong Wu

摘要

Glioblastoma (GBM) immunotherapy is limited by the blood-brain barrier (BBB) and the tumor immune resistance. Here, we develop an engineered bacterial outer membrane vesicle (OMV) through safe and straightforward genetic modification of Escherichia coli, termed OMV-C-C, enabling co-expression of cell-penetrating peptides (CPP) and chlorotoxin (CLT) on its surface. The OMV-C-C efficiently crosses BBB and specifically targets tumor cells both in vitro and in vivo. A single intravenous administration of OMV-C-C significantly inhibit GBM growth by enhancing the infiltration of CD8+ T cells in orthotopic brain tumor models. Mechanistically, interferon-gamma (IFN-γ) released by CD8+ T cells induces ferroptosis-specific lipid peroxidation in tumor cells through inhibiting cystine-glutamate exchanger (system Xc−) and downregulating glutathione peroxidase 4 (GPX4), a pathway demonstrated to be extremely activated in human GBM samples. Furthermore, IFN-γ facilitates erastin- and RSL-3-induced ferroptosis of tumor cells, particularly in temozolomide (TMZ)-resistant cells. Additionally, OMV-C-C@RSL-3 synergistically suppresses GBM growth in vivo. Thus, biosynthetically engineered OMV-C-C integrates intrinsic immunomodulatory activity with ferroptosis enhancement to strengthen glioblastoma immunotherapies, offering a versatile platform to overcome limitations in brain tumor immunotherapy.

Graphical Abstract