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<p>Cholangiocarcinoma (CCA), the second most prevalent primary hepatic malignancy, demonstrates resistance to antiangiogenic therapy due possibly to the dynamic interaction between cancer-associated fibroblast (CAF)-mediated extracellular matrix (ECM) remodeling and angiogenesis. This study shows that anti-VEGFR2 therapy activates CAF, inducing excessive ECM deposition and forming a physical barrier that diminishes the effectiveness of antiangiogenic therapy in CCA. Based on the finding, we rationally engineered vascular endothelial cell-derived nanovesicles that inherit the angiogenic factor receptor that competitively bind and neutralize pro-angiogenic ligands to diminish their bioeffects. These nanovesicles also retain high levels of integrin αvβ3 and specifically carry peptide B7-33 (an inducer of fibroblasts quiescence) modified by the cRGD peptide, thereby developing dual-functional nanovesicles (B7-33-SNPs). The study revealed that B7-33-SNPs synergistically disrupted the CAF-angiogenesis crosstalk, effectively reducing microvessel density and fibrotic deposition in subcutaneous xenograft CCA models. This combinatorial strategy achieved a 67.7 ± 17.6% tumor growth inhibition rate through simultaneous targeting of stromal desmoplasia and vascular niches (<i>p</i> &lt; 0.001 vs. PBS group). This tumor microenvironment reshaping strategy, which concurrently inhibits CAF activation and angiogenesis, offers a promising alternative for suppressing malignant CCA.</p> Graphical abstract <p></p>

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Dual-functional nanovesicles simultaneously inhibit stromal fibrosis and angiogenesis to suppress cholangiocarcinoma progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Lijing Zhang,
  • Xixi Duan,
  • Qiying Shi,
  • Xiaohan Yao,
  • Qiang Chen,
  • Jiajia Wan,
  • Fazhan Wang,
  • Chen Ni,
  • Yongjuan Li,
  • Ming Wang,
  • Yuqiao Sheng,
  • Wenfu Zheng,
  • Juan Liu,
  • Tianjiao Ji,
  • Zhihai Qin

摘要

Cholangiocarcinoma (CCA), the second most prevalent primary hepatic malignancy, demonstrates resistance to antiangiogenic therapy due possibly to the dynamic interaction between cancer-associated fibroblast (CAF)-mediated extracellular matrix (ECM) remodeling and angiogenesis. This study shows that anti-VEGFR2 therapy activates CAF, inducing excessive ECM deposition and forming a physical barrier that diminishes the effectiveness of antiangiogenic therapy in CCA. Based on the finding, we rationally engineered vascular endothelial cell-derived nanovesicles that inherit the angiogenic factor receptor that competitively bind and neutralize pro-angiogenic ligands to diminish their bioeffects. These nanovesicles also retain high levels of integrin αvβ3 and specifically carry peptide B7-33 (an inducer of fibroblasts quiescence) modified by the cRGD peptide, thereby developing dual-functional nanovesicles (B7-33-SNPs). The study revealed that B7-33-SNPs synergistically disrupted the CAF-angiogenesis crosstalk, effectively reducing microvessel density and fibrotic deposition in subcutaneous xenograft CCA models. This combinatorial strategy achieved a 67.7 ± 17.6% tumor growth inhibition rate through simultaneous targeting of stromal desmoplasia and vascular niches (p < 0.001 vs. PBS group). This tumor microenvironment reshaping strategy, which concurrently inhibits CAF activation and angiogenesis, offers a promising alternative for suppressing malignant CCA.

Graphical abstract