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Dual-functional nanovesicles simultaneously inhibit stromal fibrosis and angiogenesis to suppress cholangiocarcinoma
Lijing Zhang1, Xixi Duan1, Qiying Shi1
1Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China.
Abstract:
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.
Insights
Cholangiocarcinoma (CCA) resists antiangiogenic therapy due to cancer-associated fibroblast (CAF) interactions. Novel dual-functional nanovesicles (B7-33-SNPs) target CAF and angiogenesis, significantly inhibiting CCA tumor growth.
Area of Science:
- Oncology
- Biotechnology
- Nanomedicine
Background:
- Cholangiocarcinoma (CCA) is a primary liver cancer resistant to antiangiogenic therapy.
- This resistance stems from cancer-associated fibroblast (CAF)-mediated extracellular matrix (ECM) remodeling and angiogenesis.
- Anti-VEGFR2 therapy can paradoxically activate CAFs, worsening ECM deposition and therapy resistance.
Purpose of the Study:
- To engineer dual-functional nanovesicles (B7-33-SNPs) to overcome CCA resistance to antiangiogenic therapy.
- To investigate the synergistic effect of targeting CAF activation and angiogenesis in CCA.
- To evaluate the efficacy of B7-33-SNPs in preclinical CCA models.
Main Methods:
- Engineered vascular endothelial cell-derived nanovesicles (B7-33-SNPs) carrying specific peptides and targeting ligands.
- B7-33-SNPs were designed to neutralize pro-angiogenic factors and induce fibroblast quiescence.
- Evaluated B7-33-SNPs in subcutaneous xenograft CCA models for effects on tumor growth, microvessel density, and fibrotic deposition.
Main Results:
- B7-33-SNPs effectively disrupted the crosstalk between CAFs and angiogenesis.
- Significant reduction in microvessel density and fibrotic deposition was observed.
- Achieved a 67.7% tumor growth inhibition rate, demonstrating synergistic efficacy.
Conclusions:
- Dual-functional nanovesicles (B7-33-SNPs) offer a promising strategy for reshaping the tumor microenvironment in CCA.
- Simultaneous targeting of CAF activation and angiogenesis overcomes therapeutic resistance.
- This approach presents a novel therapeutic alternative for advanced cholangiocarcinoma.
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