A Synergistic DNA-polydopamine-MnO₂ Nanocomplex for Near-Infrared-Light-Powered DNAzyme-Mediated Gene Therapy

Abstract

DNAzyme is emerging for gene therapy. The administration of the in vivo catalytic activity of DNAzyme has proven important but challenging for clinical applications. Herein, we report a synergistic DNA-polydopamine-MnO2 nanocomplex, which enables near-infrared (NIR)-light-powered catalytic activity of DNAzyme in vivo. The nanocomplex has a hierarchical structure: a DNA nanoframework as the scaffold and polydopamine-MnO2 (PM) as the coating layer. The DNA nanoframework contains repeated DNAzyme sequences. PM assembles on the surface of the DNA nanoframework. When the nanocomplex accumulates at tumor sites, upon NIR-light radiation, polydopamine induces a temperature elevation at tumor sites via photothermal conversion; meanwhile, glutathione triggers decomposition of PM to release Mn2+ to activate DNAzyme in the cytoplasm for gene regulation. In vitro and in vivo experiments show that the PM-induced temperature elevation enhances the Egr-1 mRNA cleavage activity of DNAzyme, promoting downregulation of the Egr-1 protein in tumor cells. In addition, the temperature elevation induces heat stress, achieving a synergistic tumor ablation effect.

Self-Protected DNAzyme Walker with a Circular Bulging DNA Shield for Amplified Imaging of miRNAs in Living Cells and Mice

“…To generate an amplified signal output, some protein enzyme-mediated isothermal signal amplification methods, such as rolling circle amplification (RCA) , and isothermal circular strand displacement polymerization (ICSDP), have been employed for miRNA detection. However, protein enzymes are susceptible to changes in the surrounding microenvironment and often exhibit a compromised catalytic activity in cellular milieu. , Recently, DNAzyme-mediated catalytic (DNAzymatic) reaction, as an emerging class of protein enzyme-free signal amplification methods, has been explored. ,− Among them, RNA-cleaving DNAzymes are of particular interest for the detection of miRNAs due to their excellent activity and flexible programmability. − However, the application of DNAzymes in the intracellular detection of miRNAs still faces two major issues. First, owing to the highly negative charge backbone and hydrophilic nature of the nucleobases, it is difficult for DNAzymes to traverse the lipophilic cell membrane.…”

DNA-based enzymatic systems and their applications

“…By the integration of photodynamic therapy (PDT) with gene therapy, the tumors are inhibited to a great degree. Recently, Yang's group reported an ultralong DNA sequence containing repeated Mn 2+ -specific Dz sequences for enhanced gene therapy by regulating the catalytic performance of the NIR-light-driven Dzs in vivo ( Zhao et al., 2021 ). Here, MnO 2 nanoparticles with polydopamine coating were assembled on the surface of DNA nanostructures that can respond to GSH and release Mn 2+ to activate the Mn 2+ -specific Dzs, cleaving the target EGR-1 mRNA.…”

Dynamic Transformation of DNA Nanostructures inside Living Cells

“…Reproduced from Ref. [18] with permission, copyright 2021 American Chemical Society. can greatly improve delivery efficiency and reduce systemic side effects.…”

“…In 2021, we developed a DNA-polydopamine-MnO 2 nanocomplex (DP-PM) for gene therapy (Figure 2B). [18] Polydopamine modified MnO 2 (PM) was prepared through a redox reaction of dopamine and KMnO 4 . Furthermore, PM could assemble with DNAzyme sequence containing DNA nanoflower to form DP-PM by π-π stacking interactions.…”

“…with permission, copyright 2018 American Chemical Society; B) GSH-activated DP-PM for synergistic gene-photothermal therapy. Reproduced from Ref [18]. with permission, copyright 2021 American Chemical Society.…”