Citation: Xiuyan Wan, Xincheng Qiao, Yu Zhang, Wei Pan, Na Li, Bo Tang. Logic-gated, triple-responsive DNAzyme nanoplatform for precise hepatocellular carcinoma treatment[J]. Chinese Chemical Letters, ;2026, 37(10): 112093. doi: 10.1016/j.cclet.2025.112093 shu

Logic-gated, triple-responsive DNAzyme nanoplatform for precise hepatocellular carcinoma treatment

Xiuyan Wan ^{a, 1} ,
Xincheng Qiao ^{a, 1} ,
Yu Zhang ^a ,
Wei Pan ^a ,
Na Li ^{a, *,} ,
Bo Tang ^{a, b}

a.
College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Ji’nan 250014, China
b.
Laoshan Laboratory, Qingdao 266237, China

lina@sdnu.edu.cn

Received Date: 29 July 2025
Revised Date: 5 November 2025
Accepted Date: 7 November 2025
Available Online: 8 November 2025

Figures(5)

Precise gene therapy for hepatocellular carcinoma (HCC) remains challenging due to the lack of tumor-selective activation and biosafety concerns of conventional DNAzyme systems. Herein, we report a logic-gated, triple-responsive nanoplatform that enables spatiotemporal control of DNAzyme activation exclusively within the tumor microenvironment. The DNAzyme is rendered catalytically inactive through boronate caging and is loaded into an N-acetylgalactosamine (GalNAc)-functionalized zinc metal-organic framework (Zn-MOF) for HCC-targeted delivery. The system integrates three tumor-associated stimuli, acidic pH, Zn²⁺ release, and reactive oxygen species (ROS) generation, as a cascaded logic gate to ensure sequential and tumor-specific activation. Acidic pH triggers Zn-MOF degradation, releasing both Zn²⁺ and the caged DNAzyme. Zn²⁺ catalyzes ROS generation, which decages the DNAzyme and enables its Zn²⁺-dependent cleavage of oncogenic early growth response protein 1 (EGR-1) mRNA. This logic-gated activation strategy ensures high specificity, minimal off-target effects, and synergistic antitumor efficacy by combining chemodynamic therapy and gene silencing. The proposed nanoplatform offers a robust blueprint for highly selective and safe DNAzyme-based cancer therapies.
- Logic-gated,
- Triple-stimuli-responsive,
- DNAzyme,
- Metal-organic framework,
- Gene therapy,
- Hepatocellular carcinoma
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