Scholarlink

Background <p>Gastric cancer, the fifth most prevalent cancer globally, poses significant treatment challenges due to factors such as late diagnosis, early metastasis, limited surgical options, and the systemic toxicity of chemotherapy. Because luminal barriers are often compromised in gastric cancers , orally administered therapies that enable localized absorption and drug release represent a promising new direction for site-specific treatment with limited side effects.</p> Results <p>We introduce a disulfide-linked thermostable exoshell system that orally delivers protein-based bioorthogonal catalytic centres directly to cancer tissues. The highly engineered exoshells effectively encapsulated and stabilized labile catalytic centres, preventing degradation in the harsh gastric environment. In vivo gastric tumors were treated using the anti-cancer properties of active metabolites of the prodrug indole-3-acetic acid (IAA) converted in situ via bioorthogonal catalysis. In vitro cell studies revealed a dose- and time-dependent inhibition of gastric cancer cell growth, irrespective of their HER2 status. This inhibition was accompanied by upregulation of mitochondrial lipid peroxidation, reduced mitochondrial membrane potential, and activation of necroptotic pathway markers such as RIP1, RIP3, and MLKL at both mRNA and protein levels. In a mouse model of gastric cancer induced by N-Methyl-N-Nitrosourea, oral administration of catalytic exoshells for 6 weeks significantly inhibited gastric inflammation and tumour polyp growth. Additionally, LC/MS/MS-based metabolomic analysis of plasma obtained from treated mice showed significant upregulation of cytotoxic metabolites of IAA. Notably, metabolites relevant to redox regulation, including alpha-tocopherol (vitamin E), glutathione (GSH), homocysteine, methyl cysteine, and cysteine sulfinic acid, were identified as the top differentially expressed metabolites, indicating potent suppression of inflammation and tumour growth. Histological analysis of gastric tissue showed a reduced number of polyps and subsequent development of gastric tumours.</p> Conclusion <p>Our in vitro and in vivo results demonstrated that exoshells possessed significant potential as an orally administered, titratable therapeutic platform for the management of gastrointestinal cancers.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Bioorthogonal catalytic centres engineered for gastrointestinal stabilization provide oral delivery for the treatment of gastric cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月28日

查看全文
  • Muthu Kumaraswamy Shanmugam,
  • Girish Vallerinteavide Mavelli,
  • Pang Yuze,
  • Hrucha Shielesh Damle,
  • Leroy Sivappiragasam Pakkiri,
  • Lik Hang Wu,
  • Lim Poh Leong,
  • Siddhesh Sujit Vaidya,
  • Samira Sadeghi,
  • Gautam Sethi,
  • Chester Lee Drum

摘要

Background

Gastric cancer, the fifth most prevalent cancer globally, poses significant treatment challenges due to factors such as late diagnosis, early metastasis, limited surgical options, and the systemic toxicity of chemotherapy. Because luminal barriers are often compromised in gastric cancers , orally administered therapies that enable localized absorption and drug release represent a promising new direction for site-specific treatment with limited side effects.

Results

We introduce a disulfide-linked thermostable exoshell system that orally delivers protein-based bioorthogonal catalytic centres directly to cancer tissues. The highly engineered exoshells effectively encapsulated and stabilized labile catalytic centres, preventing degradation in the harsh gastric environment. In vivo gastric tumors were treated using the anti-cancer properties of active metabolites of the prodrug indole-3-acetic acid (IAA) converted in situ via bioorthogonal catalysis. In vitro cell studies revealed a dose- and time-dependent inhibition of gastric cancer cell growth, irrespective of their HER2 status. This inhibition was accompanied by upregulation of mitochondrial lipid peroxidation, reduced mitochondrial membrane potential, and activation of necroptotic pathway markers such as RIP1, RIP3, and MLKL at both mRNA and protein levels. In a mouse model of gastric cancer induced by N-Methyl-N-Nitrosourea, oral administration of catalytic exoshells for 6 weeks significantly inhibited gastric inflammation and tumour polyp growth. Additionally, LC/MS/MS-based metabolomic analysis of plasma obtained from treated mice showed significant upregulation of cytotoxic metabolites of IAA. Notably, metabolites relevant to redox regulation, including alpha-tocopherol (vitamin E), glutathione (GSH), homocysteine, methyl cysteine, and cysteine sulfinic acid, were identified as the top differentially expressed metabolites, indicating potent suppression of inflammation and tumour growth. Histological analysis of gastric tissue showed a reduced number of polyps and subsequent development of gastric tumours.

Conclusion

Our in vitro and in vivo results demonstrated that exoshells possessed significant potential as an orally administered, titratable therapeutic platform for the management of gastrointestinal cancers.

Graphical Abstract