Targeting Glioblastoma Stem Cells via EphA2: Structural Insights into the RNA Aptamer A40s for Precision Therapy

EphA2 receptor tyrosine kinase is overexpressed in many solid tumors and serves as a key driver of tumorigenesis and metastasis. It is highly expressed in glioblastoma multiforme, the most aggressive brain tumor in adults, and in its stem cells [glioblastoma stem cells (GSCs)], which contribute to treatment resistance and tumor relapse. In a previous study, we used the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) procedure, a method for selecting high-affinity nucleic acids to specific targets via iterative selection and amplification, to identify the 2′-fluorinated EphA2-targeting RNA aptamer A40L and a truncated 30-mer derivative, A40s. Both aptamers were able to inhibit GSC growth, stemness, and migration upon EphA2 binding. Here, by integrating computational and experimental methods, the A40s structure was unraveled and its interaction with EphA2 was investigated. Our model offers a blueprint to accelerate the development of optimized A40s variants, advancing next-generation EphA2-targeted anticancer therapies.