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<p>The immunosuppressive tumor microenvironment (TME) of gliomas makes their treatment consistently suboptimal, and the aberrant energy metabolism of glioma cells orchestrates tumorigenesis and the immunosuppressive TME. In this work, we construct a biodegradable nano-modulator (ZIF-90@MnO<sub>2</sub>@GPNA, ZMG) based on ZIF-90 decorated by MnO<sub>2</sub> and loaded with glutamine transport antagonist (L-γ-glutamyl-<i>p</i>-nitroanilide, GPNA) for efficiently gliomas therapy by multi-pathways inhibition of energy metabolism and reshaping TME. In order to efficiently cross the blood-brain barrier (BBB) and target the gliomas, hyaluronic acid (HA) and lactoferrin (Lf) are further functionalized on its surface (ZIF-90@MnO<sub>2</sub>@GPNA@HA-Lf, ZMGH-Lf). ZMGH-Lf biodegrades in response to stimulation of TME, releasing Mn<sup>2+</sup>, which can catalyze H<sub>2</sub>O<sub>2</sub> to ·OH and lead to mitochondrial dysfunction. ZMGH-Lf can inhibit glycolysis by alleviating hypoxia and reducing NAD<sup>+</sup> expression, while loaded GPNA inhibits the compensatory increase in glutamine uptake. This therapeutic strategy not only achieves a multi-pathway disruption of glioma metabolism, but also relieves the immune resistance and improves the immune TME. All these findings demonstrate that ZMGH-Lf can effectively inhibit gliomas by multi-ways manipulation of energy metabolism and immunotherapy, which provides a new strategy for the treatment of gliomas.</p>

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Biodegradable hollow MOFs-based nano-modulator for collaboratively blocking energy metabolism for immunotherapy of orthotopic gliomas

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • Shiqi Bai,
  • Hongya Zhang,
  • Rong Mou,
  • Shaopeng Zhang,
  • Na Yin,
  • Yue Cao,
  • Wanying Li,
  • Ziqian Wang,
  • Bin Wang,
  • Donghao Qu,
  • Shuyan Song,
  • Yunqian Li,
  • Xinrui Liu,
  • Yanfang Jiang,
  • Yinghui Wang,
  • Hongjie Zhang

摘要

The immunosuppressive tumor microenvironment (TME) of gliomas makes their treatment consistently suboptimal, and the aberrant energy metabolism of glioma cells orchestrates tumorigenesis and the immunosuppressive TME. In this work, we construct a biodegradable nano-modulator (ZIF-90@MnO2@GPNA, ZMG) based on ZIF-90 decorated by MnO2 and loaded with glutamine transport antagonist (L-γ-glutamyl-p-nitroanilide, GPNA) for efficiently gliomas therapy by multi-pathways inhibition of energy metabolism and reshaping TME. In order to efficiently cross the blood-brain barrier (BBB) and target the gliomas, hyaluronic acid (HA) and lactoferrin (Lf) are further functionalized on its surface (ZIF-90@MnO2@GPNA@HA-Lf, ZMGH-Lf). ZMGH-Lf biodegrades in response to stimulation of TME, releasing Mn2+, which can catalyze H2O2 to ·OH and lead to mitochondrial dysfunction. ZMGH-Lf can inhibit glycolysis by alleviating hypoxia and reducing NAD+ expression, while loaded GPNA inhibits the compensatory increase in glutamine uptake. This therapeutic strategy not only achieves a multi-pathway disruption of glioma metabolism, but also relieves the immune resistance and improves the immune TME. All these findings demonstrate that ZMGH-Lf can effectively inhibit gliomas by multi-ways manipulation of energy metabolism and immunotherapy, which provides a new strategy for the treatment of gliomas.