Engineering self-catabolic DNAzyme nanospheres for synergistic anticancer therapy

DNAzyme-based gene therapy faces some challenges including cell penetration, activity limitation, and co-delivery functions. Self-assembled DNA nanomedicine has attracted widespread attention due to its many advantages. It is urgent to develop a universal DNA degradation strategy for precise programmable drug release. Herein, we reported a self-catabolic DNAzyme nanospheres (SCNS), which could simultaneously achieve cell penetration, activity enhancement, and co-delivery functions. The SCNS were assembled through Y-DNA stepwise hybridization with each other, which were then loaded with aptamer (Apt), doxorubicin (Dox), and zinc oxide nanoparticles (ZnO NPs). The acid-triggered dissociation of ZnO NPs leads to the generation of Zn²⁺ ions cofactors for immediately self-catabolic DNAzyme nanospheres. After the disassembly of the SCNS, three types of anticancer treatments would be activated, which include Zn²⁺ involved reactive oxygen species (ROS), Dox-induced chemotherapy, and DNAzyme-based gene therapy. The experimental results show that the nanoplatform (Apt-SCNS-Dox-ZnO) has a good tumor-killing effect and minimal side effects. As a smart self-driven drug delivery nanoplatform, it is anticipated to displace extraordinary potential in biomedicine and bioengineering.