In this study, we combined post-transcriptional regulation with an RNA replacement strategy by developing TERT-targeting trans-splicing ribozymes regulated by liver-specific miR-122a (Fig. 1) and evaluated the cellular and in vivo specificity and efficacy as a tool for targeted HCC gene therapy to address the cancer-selectivity challenge raised by the TERT-targeting approach. The gene discussed is TERT; the disease is hepatocellular carcinoma.