An Inducible CRISPR‐dCas9‐Based Transcriptional Repression System for Cancer Therapy

Abstract Gene therapy has been adapted for improving malignant tumor treatment. However, pharmacotherapies targeting cancer remain limited and are generally inapplicable for rare disease patients. Oleanolic acid (OA) is a plant‐derived triterpenoid that is frequently used in Chinese medicine as a safe but slow‐acting treatment for many disorders. Here, the congruent pharmacological activities of OA and CRISPR‐dCas9 in targeting AURKA or KDM1A and improving disease‐specific prognosis and used a synthetic‐biology‐inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs are utilized. In particular, the OA‐triggered CRISPR‐dCas9 transcriptional repression system rapidly and simultaneously attenuated lung and thyroid cancer. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficiencies of single therapeutics.