A smart mRNA-initiated DNAzyme nanogenerator for precise imaging and gene therapy in vivo

Despite the significant potential of gene therapy mediated by deoxyribozyme (DNAzyme) in various diseases, the success of clinical cancer treatment remains challenging due to its low selectivity and efficiency. In this study, a novel DNAzyme nanogenerator (NG) triggered by mRNA was developed for in vivo tumour-enhanced imaging and precise gene therapy. After entering target cells, the NG could initiate a DNAzyme catalytic reaction in response to tumour-associated mRNA targets within the cells. The DNAzyme catalytic reaction continuously cleaved the DNA substrate sandwiched by labeled dyes, resulting in significantly amplified fluorescence release and continuous generation of another effective DNAzyme, silencing VEGF-related genes. The detection limit of NG for TK1 mRNA reached 3.62 pM. Additionally, NG could selectively image at tumour sites and specifically generate DNAzyme in tumor cells. NG accurately identified tumors in vivo and significantly inhibited tumour growth with negligible toxicity, thus expanding the toolbox for on-demand gene delivery and precise therapy. [Display omitted] •A smart mRNA-initiated DNAzyme nanogenerator for precise imaging and gene therapy is developed.•This DNAzyme nanogenerator can ultra-sensitively detect TK1 mRNA down to 3.62 pM and display an excellent specificity.•It has been successfully applied to diagnose tumors in vitro and in vivo based on mRNA imaging.•The DNAzyme nanogenerator operate specificity and autonomously.•The DNAzyme nanogenerator generates the gene drug DNAzyme in situ on demand under the stimulation of tumor-associated mRNA.