Biodegradable, multifunctional DNAzyme nanoflowers for enhanced cancer therapy

Abstract

Safety and efficiency remain the critical hurdles hindering the practical application of gene agents, even though great effort has been made to develop various gene carriers. Herein, we present a novel biodegradable cancer therapeutic system based on DNA nanoflowers (DNFs) for targeted dual gene silencing. The therapeutic system was constructed by copying a rolling circle amplification template to produce long single-stranded DNAs with cell targeting and dual gene-silencing capability. The structure of the DNFs collapsed at acidic pH due to the decomposition of the co-assembled magnesium pyrophosphate, generating Mg2+ ions that act as cofactors for the DNAzymes and increase their ability to recognize and cleave target mRNAs. In vitro and in vivo studies demonstrated that the multifunctional DNFs showed promise for targeted cancer cell recognition, gene silencing, induction of apoptosis and inhibition of tumor growth. Considering the enhanced therapeutic effect and biocompatibility of this therapeutic platform, it is anticipated to be of great interest for the clinical treatment of cancers. Embedding multiple gene-silencing agents within the petal-like surfaces of a DNA nanostructure makes it easier to target tumors in live mice. Controlled laboratory studies have shown that RNA-cleaving DNAzymes can stifle the expression of genes that contribute to cancer production, but their activity in complex biological systems is debated. Jinchao Zhang from Hebei University in China and co-workers have developed a more efficient anti-tumor agent by combining two DNAzymes with a single-stranded aptamer that has an affinity for cancer cells. Using rolling circle amplification, the researchers self-assembled these components, along with magnesium pyrophosphate, into crinkled ’nanoflower‘ spheres. Both in vitro and in vivo trials revealed the material catalytically inhibited two RNAs simultaneously, boosting efficiency compared to single DNAzymes. Acidic digestion of the nanoflowers also released magnesium ions that acted as co-factors for gene silencing. We present a novel biodegradable cancer therapeutic system based on DNAzyme nanoflowers for targeted dual gene silencing. The therapeutic system was constructed by copying rolling circle amplification template to produce long single-stranded DNAs with cell targeting and dual gene silencing capability. The structure of the nanoflowers collapsed at acidic pH due to decomposition of the co-assembled magnesium pyrophosphate, generating Mg2+ ions which act as cofactors for the DNAzymes and increase their ability to recognize and cleave target mRNAs. Considering its enhanced therapeutic effect and biocompatibility, this platform is expected to be of great interest for clinical treatment of cancers.