A smart metal-polyphenol-DNAzyme nanoplatform for gene-chemodynamic synergistic tumor therapy

DNAzyme-based gene regulation shows great potential for the therapy of many cancers. However, ineffective delivery and insufficient cofactor supply pose challenges for potent gene therapy. In this study, we constructed a smart metal-polyphenol-DNAzyme nanoplatform (TA-Mn@Dz NPs) with intrinsic stability, effective delivery, and cofactor self-supply ability for gene-chemodynamic synergistic tumor therapy. Tannic acid, a plant-derived polyphenol, acts as an intermediate structural unit to mediate the assembly of Mn²⁺/DNAzyme and tumor acid environment-responsive nanocarriers. Intracellularly, the acidic environment triggers the decomposition of TA-Mn@Dz NPs to release DNAzyme and Mn²⁺. The Mn²⁺ ion not only boosts the catalytic cleavage of surviving mRNA for effective gene therapy but also activates chemodynamic therapy (CDT), generating highly toxic ·OH from endogenous H₂O₂. When tail intravenously injected into MCF-7 tumor-bearing mice, the TA-Mn@Dz NPs display desirable synergistic gene-chemodynamic antitumor effects, paving the way for developing DNAzyme-based multifunctional theranostic platforms for biomedical applications. STATEMENT OF SIGNIFICANCE: 1. A smart metal-polyphenol-DNAzyme nanoplatform was constructed for gene-chemodynamic synergistic tumor therapy. 2. Tannic acid act as intermediate structural units to mediate the assembly of Mn²⁺/DNAzyme and tumor acid environment-responsive nanocarriers. 3. The Mn²⁺-ion could not only boost the catalytic cleavage of surviving mRNA for effective gene therapy, but also catalyze endogenous H₂O₂ to form cytotoxic hydroxyl radicals for chemodynamic therapy. 4. Our work paves an extremely simple way to integrate gene therapy with CDT for the dual-catalytic tumor treatment.