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<p>Pyroptosis has emerged as a promising approach for cancer immunotherapy. However, current pyroptosis inducers lack specificity for cancer cells and have a weak antitumour immune response. Here we report a tumour-specific nanoparticle (NP-NH-D<sub>5</sub>) that activates pyroptosis by disrupting lysosomes for cancer immunotherapy. NP-NH-D<sub>5</sub> undergoes negative-to-positive charge reversal and nanoparticle-to-nanofibre transformation within tumour cell lysosomes through tandem response to extracellular matrix metallopeptidase-2 and intracellular reducing agents. The as-formed non-peptide nanofibres efficiently break the lysosomes and trigger gasdermin-D-mediated pyroptosis, leading to strong immunogenic cell death and alleviation of the immunosuppressive tumour microenvironment. In vivo, NP-NH-D<sub>5</sub> inhibits orthotopic 4T1 breast tumours, prevents metastasis and recurrence, and prolongs survival without systemic side effects. Furthermore, it greatly enhances the effectiveness of PD-L1 antibody immunotherapy in the 4T1 late-stage lung metastasis and aggressive orthotopic Pan02 pancreatic tumour models. Our research may open pathways for developing stimuli-responsive pyroptosis inducers for precise cancer immunotherapy.</p>

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Tandem-controlled lysosomal assembly of nanofibres induces pyroptosis for cancer immunotherapy

  • 期刊论文

  • 发表日期：

    2025年2月18日

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  • Junya Zhang,
  • Yuxuan Hu,
  • Xidan Wen,
  • Zeyue Yang,
  • Ziyi Wang,
  • Zhiyuan Feng,
  • He Bai,
  • Qi Xue,
  • Yinxing Miao,
  • Tian Tian,
  • Peng Zheng,
  • Jingjing Zhang,
  • Jie Li,
  • Ling Qiu,
  • Jing-Juan Xu,
  • Deju Ye

摘要

Pyroptosis has emerged as a promising approach for cancer immunotherapy. However, current pyroptosis inducers lack specificity for cancer cells and have a weak antitumour immune response. Here we report a tumour-specific nanoparticle (NP-NH-D5) that activates pyroptosis by disrupting lysosomes for cancer immunotherapy. NP-NH-D5 undergoes negative-to-positive charge reversal and nanoparticle-to-nanofibre transformation within tumour cell lysosomes through tandem response to extracellular matrix metallopeptidase-2 and intracellular reducing agents. The as-formed non-peptide nanofibres efficiently break the lysosomes and trigger gasdermin-D-mediated pyroptosis, leading to strong immunogenic cell death and alleviation of the immunosuppressive tumour microenvironment. In vivo, NP-NH-D5 inhibits orthotopic 4T1 breast tumours, prevents metastasis and recurrence, and prolongs survival without systemic side effects. Furthermore, it greatly enhances the effectiveness of PD-L1 antibody immunotherapy in the 4T1 late-stage lung metastasis and aggressive orthotopic Pan02 pancreatic tumour models. Our research may open pathways for developing stimuli-responsive pyroptosis inducers for precise cancer immunotherapy.