Abstract

Targeting RNA-binding proteins (RBPs) that control mRNA turnover presents a promising avenue for modulating gene expression and accessing otherwise “undruggable” intracellular targets. MEX3C is a tumor- and tissue-specific RBP that facilitates transcript destabilization by recruiting the CCR4–NOT deadenylation complex; however, selective tools to perturb MEX3C are lacking. Here, we report the development of a high-affinity and specific DNA aptamer through iterative Blocker-SELEX selection and sequence optimization. The resulting aptamer, MRiApt, binds the KH1 domain of MEX3C with nanomolar affinity and competitively inhibits RNA binding while sparing the homologous KH2 domain. A chemically stabilized derivative, MRiApt-PT-stem, exhibits enhanced stability and efficient intracellular uptake and effectively antagonizes the MEX3C-dependent repression of HLA-A2 transcripts, restoring HLA-A2 expression and thereby improving tumor cell recognition by T cells. Analysis of TCGA data revealed that high-MEX3C expression was significantly associated with poor prognosis in liver hepatocellular carcinoma (LIHC), underscoring the clinical relevance of perturbing MEX3C. Together, these findings establish MRiApt-PT-stem as a chemical probe to dissect and modulate MEX3C-mediated post-transcriptional regulation, providing a foundation for future approaches in transcriptome modulation and therapeutic targeting of RBPs.