Pistol Ribozyme-Driven Catalytic Spherical Nucleic Acid Integrates Gene and Chemotherapy for Enhanced Cancer Therapy
Jingjing Zhang, Minglei Zhao, Zhiqin Xi, Xiaoqian Liu, Linyi Feng, Jie Bai, Xuelin Zhan, Chunqiu Zhang, Adam C. Midgley, Yijin Liu
Abstract
Gene-targeted therapies are revolutionizing cancer treatment due to their high specificity and low toxicity. Among these, ribozymes hold promise as independent gene therapy agents capable of directly cleaving target mRNAs. The pistol ribozyme, discovered in 2015, stands out for its compact structure and robust cleavage activity, making it a promising candidate for RNA silencing under physiological conditions. However, its clinical application is limited by nuclease susceptibility and biological barrier penetration. To overcome these obstacles, this study presents an innovative gene-regulation strategy incorporating engineered pistol ribozymes into a spherical nucleic acid (SNA) nanocarrier. This catalytic SNA nanocarrier, built on a DNA core–shell framework, combines the ribozyme with doxorubicin (Dox) to form the ApRz-CS/Dox nanoplatform. The design of ApRz-CS/Dox features a homopolymerized DNA core and a reticular DNA shell, enhancing stability. Tumor-targeting aptamers are arranged on its surface, directing it specifically to cancer cells. Within the target cells, the ribozyme is released in response to overexpressed miR-21, facilitating the cleavage of polo-like kinase 1 mRNA. This integrated approach effectively combines gene therapy with the chemotherapeutic effects of Dox, addressing the challenges associated with the delivery of newly developed nucleic acid drugs and offering a promising strategy for enhanced cancer treatment.