Novel RNA aptamer HPE3 suppresses angiogenesis via inhibiting endocan–VEGF-A formation in Matrigel-implanted mice

Endocan is a vascular endothelial cell-secreted factor that is closely associated with angiogenesis and inflammation, regulates VEGF-A-mediated angiogenesis. While antibody- and siRNA-based strategies have targeted endocan, limitations in intracellular delivery and specificity have driven the development of aptamer-based therapeutics. In this study, we report the identification and validation of HPE3, a novel RNA aptamer that binds endocan with high affinity (K D = 0.67 nM). HPE3 was selected using SELEX and shown via surface plasmon resonance to interfere with the formation of the endocan–VEGF-A complex. In vitro, HPE3 suppressed VEGFR2 downstream signaling, angiogenesis-related gene expression, pseudopodia formation, and endothelial cell migration. In vivo, a Matrigel plug assay demonstrated that HPE3 reduced neovascularization by > 85% compared to untreated controls. Histological staining and hemoglobin quantification confirmed its anti-angiogenic effects. Notably, HPE3 demonstrated anti-angiogenic activity comparable to a commercial anti-VEGF drug at an equivalent or lower molar dosage. These findings indicate that HPE3 effectively inhibits both in vitro and in vivo angiogenesis by interfering with endocan–VEGF-A interactions, offering a promising therapeutic strategy for endocan-mediated diseases such as cancer and chronic inflammation.