Targeting exosomes enveloped EBV‐miR‐BART1‐5p‐antagomiRs for NPC therapy through both anti‐vasculogenic mimicry and anti‐angiogenesis

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with high incidence in China. The molecular mechanisms of vasculogenic mimicry (VM) and angiogenesis are not fully elucidated in NPC. More specially, it has seldomly been reported that Epstein–Barr virus‐encoded miRNA can regulate VM and angiogenesis in NPC. The aim of this study was to investigate the function and molecular mechanism of a targeting exosome system (iRGD‐exo‐antagomiR) against VM and angiogenesis in NPC, and to provide new approaches for improving the comprehensive treatment of NPC. METHODS: Exosomes were isolated by differential ultracentrifugation. Dynamic light scattering, transmission electron microscopy and western blotting were performed to characterize the exosomes. The 3D‐Culture assay, tube formation assay, chicken chorioallantoic membrane assay, Matrigel plug assay, mouse xenograft tumor modeling and immunohistochemical staining were applied to evaluate the anti‐VM and anti‐angiogenic effects of the targeting exosome system in vitro and in vivo. Western blot was performed to detect the changes of downstream regulated networks following interference and recovery of the target gene. RESULTS: In vitro or in vivo treatment with iRGD‐tagged exosome containing antagomiR‐BART1‐5p specifically suppressed VM and angiogenesis in NPC. EBV‐miR‐BART1‐5p promoted VM and angiogenesis in vitro and in vivo by regulating VEGF, PI3K, Akt, mTOR and HIF1‐α in a Spry2‐dependent manner. CONCLUSIONS: Our findings demonstrated that targeting exosomes enveloped EBV‐miR‐BART1‐5p‐antagomiRs in a Spry2‐dependent manner for NPC therapy through both anti‐VM and anti‐angiogenesis in vitro and in vivo.