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<p>Radiotherapy for abdominal malignancies is limited by intestinal toxicity and secondary colorectal cancers. Here, we develop an oral, microbiota-responsive nano-amifostine (CS/PEC-AMF NPs) system that achieves site-specific radioprotection in the colorectum without compromising antitumor efficacy. By conjugating amifostine to pectin and encapsulating it with chitosan, the nanoparticles enable pH- and microbiota-triggered release in the large bowel, safeguarding drug bioactivity during gastrointestinal transit. In murine models, CS/PEC-AMF NPs attenuate both acute and chronic radiation-induced bowel injury, restore epithelial integrity, preserve stem cell populations, and promote tight junction repair. Integrated metagenomic and metabolomic analyses reveal that the system normalizes gut microbiota diversity and composition, increases short-chain fatty acid production, and facilitates macrophage polarization towards the anti-inflammatory M2 phenotype. Notably, the formulation synergistically enhances tumor suppression and extends survival in orthotopic colorectal tumor models undergoing radiotherapy and reduces the incidence of secondary colorectal tumors post-irradiation. Mechanistically, transcriptomic analysis demonstrates the suppression of proinflammatory pathways and the promotion of DNA repair programs. This study provides a paradigm for leveraging functional nanomaterials to orchestrate precise, tissue-specific radioprotection and immune modulation, addressing a key challenge in abdominal cancer therapy.</p> Graphical abstract <p></p>

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Microbiota-responsive oral nano-amifostine enables colorectal-specific radioprotection and tumor immunity via gut microenvironment reprogramming

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • Kaichao Song,
  • Ling Ren,
  • Xiuping Guo,
  • Gang Ren,
  • Yanan Sun,
  • XiaoLian Tian,
  • Chujuan Hu,
  • Mingyu Pan,
  • Quanyong Yu,
  • Zhigang Luo,
  • Yumei Hao,
  • Peng Lei,
  • Haoyang Yu,
  • Sitong Yang,
  • Qingbo Chen,
  • Yuanbin Li,
  • Shan Wang,
  • Yingying He,
  • Zhouguang Hui,
  • Wensheng Zheng,
  • Jiandong Jiang,
  • Lulu Wang

摘要

Radiotherapy for abdominal malignancies is limited by intestinal toxicity and secondary colorectal cancers. Here, we develop an oral, microbiota-responsive nano-amifostine (CS/PEC-AMF NPs) system that achieves site-specific radioprotection in the colorectum without compromising antitumor efficacy. By conjugating amifostine to pectin and encapsulating it with chitosan, the nanoparticles enable pH- and microbiota-triggered release in the large bowel, safeguarding drug bioactivity during gastrointestinal transit. In murine models, CS/PEC-AMF NPs attenuate both acute and chronic radiation-induced bowel injury, restore epithelial integrity, preserve stem cell populations, and promote tight junction repair. Integrated metagenomic and metabolomic analyses reveal that the system normalizes gut microbiota diversity and composition, increases short-chain fatty acid production, and facilitates macrophage polarization towards the anti-inflammatory M2 phenotype. Notably, the formulation synergistically enhances tumor suppression and extends survival in orthotopic colorectal tumor models undergoing radiotherapy and reduces the incidence of secondary colorectal tumors post-irradiation. Mechanistically, transcriptomic analysis demonstrates the suppression of proinflammatory pathways and the promotion of DNA repair programs. This study provides a paradigm for leveraging functional nanomaterials to orchestrate precise, tissue-specific radioprotection and immune modulation, addressing a key challenge in abdominal cancer therapy.

Graphical abstract