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<p>Intelligent DNA composite nanostructures hold great promise for tumor-specific and stimulus-responsive therapeutic delivery, yet their rational design and stable fabrication remain challenging. Here, we report a facile strategy to construct Cu–Mn DNA nanoflowers (Cu–Mn DNFs) by integrating a polyvalent tandem aptamer, pH-responsive copper nanoparticles (CuNPs), and a manganese pyrophosphate mineral core. Unlike conventional base-paired DNA assemblies, the Cu–Mn DNFs possess a densely packed, non-Watson–Crick framework that ensures excellent biostability under physiological conditions. The tandem aptamers confer precise tumor-cell targeting, while the acidic lysosomal microenvironment triggers site-specific degradation, releasing Cu<sup>2+</sup> and Mn<sup>2+</sup> ions. The released ions cooperatively catalyze Fenton-like reactions, generating abundant reactive oxygen species (ROS) and depleting glutathione (GSH) to amplify oxidative stress. Furthermore, mitochondrial accumulation of Cu<sup>2+</sup> induces cuproptosis, resulting in synergistic tumor cell death. This work demonstrates a programmable, multifunctional metal–DNA hybrid platform that couples tumor recognition, microenvironment responsiveness, and self-amplified catalytic therapy. The Cu–Mn DNF system offers a promising paradigm for precision cancer treatment and broader applications in biomedical nanotechnology.</p>

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Cell-specific Cu–Mn DNA nanoflowers for enhanced tumor cuproptosis via ROS amplification and GSH depletion

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Wenhao Dai,
  • Tongtong Zhang,
  • Fan Zhang,
  • Xueji Zhang,
  • Haifeng Dong

摘要

Intelligent DNA composite nanostructures hold great promise for tumor-specific and stimulus-responsive therapeutic delivery, yet their rational design and stable fabrication remain challenging. Here, we report a facile strategy to construct Cu–Mn DNA nanoflowers (Cu–Mn DNFs) by integrating a polyvalent tandem aptamer, pH-responsive copper nanoparticles (CuNPs), and a manganese pyrophosphate mineral core. Unlike conventional base-paired DNA assemblies, the Cu–Mn DNFs possess a densely packed, non-Watson–Crick framework that ensures excellent biostability under physiological conditions. The tandem aptamers confer precise tumor-cell targeting, while the acidic lysosomal microenvironment triggers site-specific degradation, releasing Cu2+ and Mn2+ ions. The released ions cooperatively catalyze Fenton-like reactions, generating abundant reactive oxygen species (ROS) and depleting glutathione (GSH) to amplify oxidative stress. Furthermore, mitochondrial accumulation of Cu2+ induces cuproptosis, resulting in synergistic tumor cell death. This work demonstrates a programmable, multifunctional metal–DNA hybrid platform that couples tumor recognition, microenvironment responsiveness, and self-amplified catalytic therapy. The Cu–Mn DNF system offers a promising paradigm for precision cancer treatment and broader applications in biomedical nanotechnology.