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.