Disruption of the Nucleolin-CXCR4 interaction by the DNA aptamer HY-4 halts colorectal cancer metastasis.

Colorectal cancer, characterized by its aggressive metastatic behavior and often poor prognosis, urgently necessitates improved diagnostic and therapeutic strategies. This study introduces HY-4, an aptamer developed via a non-Systematic Evolution of Ligands by Exponential Enrichment (SELEX) method, which shows exceptional specificity and affinity for nucleolin (NCL), a highly expressed oncogenic protein in various cancers. With remarkable biocompatibility, HY-4 significantly reduces the migration and invasion of LoVo cancer cells by disrupting the NCL-CXCR4 interaction, a pivotal pathway in cancer metastasis. This disruption highlights the potential of HY-4 to inhibit cancer metastasis without producing adverse effects. Notably, HY-4 distinguishes itself from conventional NCL-targeting aptamers by avoiding the typical G-quadruplex structure and instead adopting a unique non-G-quadruplex conformation to create a novel binding site. This unique structural conformation provides critical insight into NCL-targeting mechanisms and could profoundly influence the landscape of targeted cancer therapy. By utilizing advanced techniques such as circular dichroism spectroscopy and molecular docking simulations, we obtained detailed insights into the structural dynamics and inhibitory interactions of HY-4, thereby deepening our understanding of the crucial structure-activity relationships in NCL-targeted drug development. In summary, HY-4 represents a promising advancement in targeted therapy, potentially heralding a paradigm shift in the treatment and diagnosis of colorectal cancer.