Nonviolent Self-Catabolic DNAzyme Nanosponges for Smart Anticancer Drug Delivery

The development of self-assembled DNA nanomedicine requires a facile and accurate DNA degradation strategy for precisely programmable drug release. Conventional DNA catabolic strategies are restrained with the fragile and unclear enzymatic reactions that might lead to inefficient and uncontrollable digestion of DNA scaffolds and thus might bring undesirable side effects to the sophisticated biosystems. Herein we reported a versatile self-sufficient DNAzyme-driven drug delivery system consisting of the rolling circle polymerized DNAzyme-substrate scaffolds and the encapsulated pH-responsive ZnO nanoparticles (NPs). The full DNAzyme nanosponges (NSs) were also encoded with multivalent tandem aptamer sequences to facilitate their efficient delivery into cancer cells, where the acidic endo/lysosomal microenvironment stimulates the dissolution of ZnO into Zn²⁺ ions as DNAzyme cofactors and therapeutic reactive oxygen species generators. The supplement Zn²⁺ cofactors mediated the nonviolent DNAzyme-catalyzed cleavage of DNA scaffolds for precise and efficient drug administrations with synergistically enhanced therapeutic performance. The facile design of DNAzyme, together with their cost-effective and intrinsic robust features, is anticipated to provide extensive insights for the development of DNA-based therapeutic platforms by activating the specific intracellular biocatalytic reactions. As an intelligent and nonviolent self-driven drug delivery platform, the present DNAzyme NS system could be engineered with more therapeutic sequences and agents and was anticipated to show exceptional promise and versatility for applications in biomedicine and bioengineering.