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

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.