Engineered anchoring aptamers induce relocalization and functional inactivation of transcription factors

Proper nucleocytoplasmic distribution of transcription factors (TFs) is crucial for cellular homeostasis. Mislocalization of TFs contributes to cancers, making TF relocalization a promising anticancer therapeutic strategy. We engineered anchoring aptamers as a platform for relocalizing TFs. Anchoring aptamers are heterobifunctional nucleic acids consisting of two ligands joined by a linker: one targeting the plasma membrane-anchored protein and the other recruiting the TF. As a proof of concept, we used the Ra1 aptamer targeting Ras and the DNA ligand specific for p65 or E2F1 to construct anchoring aptamers. Simultaneous binding of the anchoring aptamers to Ras and either p65 or E2F1 effectively induces cytoplasmic relocalization and functional inactivation of p65 or E2F1. Using a lentiviral expression system of anchoring aptamers, we achieved sustained cytoplasmic retention of p65 and marked inhibition of tumor growth. This work establishes a universal platform for TF relocalization, offering promising opportunities for innovative anticancer therapeutic strategies.