Extracellular vesicle-derived circ6853 drives vascular remodeling and serves as a potential biomarker and therapeutic target for gastric cancer

Gastric cancer (GC), a leading global malignancy, urgently requires the discovery of novel diagnostic and therapeutic targets. The roles of extracellular vesicle (EV)- derived circular RNAs (circRNAs) as diagnostic biomarkers and functional regulators, particularly in vascular remodeling, remain largely undefined. Through circRNA profiling of clinical plasma-derived EVs, this study revealed that EV-circ6853 was elevated in GC plasma and peaked at advanced stages. Its expression level is correlated with poor prognosis, tumor size, and TNM stage. Detection using ddPCR demonstrated superior analytical sensitivity (limit of detection: 4.79 copies/µL). Functionally, EV‑circ6853 was found to play a dual role in regulating the GC vasculature. It functions as a sponge for miR‑627‑5p, activating the FLVCR1/Notch/HIF1A/VEGFA axis to promote angiogenesis while disrupting endothelial cell junctions. Concurrently, it stabilizes HIF1A mRNA by binding to the FUS protein, further enhancing VEGFA‑driven vascular activation. Therapeutically, we constructed a functionalized EV nanoplatform modified with iRGD via genetic engineering and efficiently loaded it with circ6853 siRNA using electroporation. This system achieved active tumor targeting and potent tumor suppression, with favorable biosafety. Our preclinical findings suggest that EV-circ6853 represents a promising preliminary candidate liquid biopsy biomarker and mediates vascular remodeling in gastric cancer. The engineered EV delivery platform provides a novel proof‑of‑concept intervention strategy for RNA-based targeted therapy of GC.