Design and Evaluation of RNA Aptamer-Mediated Delivery of C/EBPβ siRNA for Oncological Therapy

The CCAAT/enhancer-binding protein beta (CEBPB or C/EBPβ) is a transcription factor that plays a critical role in cellular differentiation, metabolism, and immune response. Emerging evidence has highlighted its complex involvement in both solid and hematological cancers, such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC), where it can act as an oncogene or a tumor suppressor, depending on the context. In this study, we describe the design and evaluation of a conjugate formed by a small interfering RNA (siRNA) for CEBPB and a transferrin receptor targeting aptamer (TfR-siCEBPB). The designed conjugate is active in human and mouse cells, by transfection and by passive uptake, demonstrating target engagement with strong downregulation of CEBPB mRNA transcript. In murine models of metastatic PDAC and cirrhotic HCC, treatment with TfR-siCEBPB was associated with reduction in tumor burden and improvement in liver function biomarkers. This novel aptamer conjugate allows delivery of targeted oligonucleotide therapy and is a promising therapeutic tool to take forward to human trials.