biostudies-literatureLuo DNational Natural Science Foundation of China5155-5163https://www.ebi.ac.uk/biostudies/studies/S-EPMC9093187biostudies-literatureUnknown13(18)Nucleic acid therapeutics has reached clinical utility through modulating gene expression. As a potential oligonucleotide drug, DNAzyme has RNA-cleaving activity for gene silencing, but faces challenges due to the lack of a safe and effective delivery vehicle and low <i>in vivo</i> catalytic activity. Here we describe DNAzyme-mediated gene regulation using dynamic DNA nanomaterials with intrinsic biocompatibility, stability, tumor-targeted delivery and uptake, and self-enhanced efficacy. We assemble programmable DNA nanosponges to package and deliver diverse nucleic acid drugs and therapeutic agents such as aptamer, DNAzyme and its cofactor precursor, and photosensitizer in one pot through the rolling circle amplification reaction, formulating a controllable nanomedicine using encoded instructions. Upon environmental stimuli, DNAzyme activity increases and RNA cleavage accelerates by a supplementary catalytic cofactor. In addition, this approach induces elevated O₂ and ¹O₂ generation as auxiliary treatment, achieving simultaneously self-enhanced gene-photodynamic cancer therapy. These findings may advance the clinical trial of oligonucleotide drugs as tools for gene modulation.Chemical scienceA dynamic DNA nanosponge for triggered amplification of gene-photodynamic modulation.PMC90931872187410322074112Liu XZou ZHu JLin XWang FMo FSong GZhao YLuo DfalseA dynamic DNA nanosponge for triggered amplification of gene-photodynamic modulation.Nucleic acid therapeutics has reached clinical utility through modulating gene expression. As a potential oligonucleotide drug, DNAzyme has RNA-cleaving activity for gene silencing, but faces challenges due to the lack of a safe and effective delivery vehicle and low <i>in vivo</i> catalytic activity. Here we describe DNAzyme-mediated gene regulation using dynamic DNA nanomaterials with intrinsic biocompatibility, stability, tumor-targeted delivery and uptake, and self-enhanced efficacy. We assemble programmable DNA nanosponges to package and deliver diverse nucleic acid drugs and therapeutic agents such as aptamer, DNAzyme and its cofactor precursor, and photosensitizer in one pot through the rolling circle amplification reaction, formulating a controllable nanomedicine using encoded instructions. Upon environmental stimuli, DNAzyme activity increases and RNA cleavage accelerates by a supplementary catalytic cofactor. In addition, this approach induces elevated O₂ and ¹O₂ generation as auxiliary treatment, achieving simultaneously self-enhanced gene-photodynamic cancer therapy. These findings may advance the clinical trial of oligonucleotide drugs as tools for gene modulation.2022-01-01T00:00:00Z2022 May2024-12-04T09:14:33.44Z2024-12-04T09:14:33.44ZS-EPMC90931873565557310.1039/d2sc00459c