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Published on: May 30, 2025
Logic-Responsive Superspherical Nucleic Acid Enables Tumor-Specific Multiplexed Gene Silencing for Efficient Cancer
Xian-Ming Guo1, Mei-Ling Zhao1, Xia Yang1
1MOE Key Laboratory of Luminescence Analysis and Molecular Sensing, College of Chemistry and Chemical Engineering, Southwest University, Chongqing, People's Republic of China.
Angewandte Chemie (International Ed. in English)
|July 21, 2026
Summary
This study introduces a novel superspherical nucleic acid (SSNA) that precisely targets multiple cancer genes. This advanced therapy demonstrates significant tumor suppression and improved survival rates with minimal side effects.
Area of Science:
- Biotechnology
- Molecular Biology
- Oncology
Background:
- Gene-targeted therapies show promise for "undruggable" oncogenes but face challenges from off-target toxicity and tumor heterogeneity.
- Developing precise and effective cancer therapies requires strategies to overcome these limitations.
Purpose of the Study:
- To develop a logic-responsive superspherical nucleic acid (SSNA) platform for tumor-specific, multiplexed gene silencing.
- To evaluate the therapeutic efficacy and specificity of the SSNA in preclinical cancer models.
Main Methods:
- Designed an SSNA with a nuclease-resistant core and a Y-shaped DNA circuit shell responsive to apurinic/apyrimidinic endonuclease 1 (APE1).
- Engineered the SSNA to release split antisense oligonucleotides for thymidine kinase 1 (TK1) and DNAzymes for survivin mRNA upon APE1 activation.
- Assessed in vitro and in vivo gene silencing, tumor growth suppression, and survival in a murine xenograft model.
Main Results:
- The SSNA demonstrated selective activation by tumor-expressed APE1, leading to dual-gene silencing of TK1 and survivin at transcriptional and translational levels.
- Exceptional tumor specificity and minimal off-target effects were observed.
- In a murine MCF-7 xenograft model, SSNA significantly suppressed tumor growth and extended median survival by 70% compared to single-target therapies.
Conclusions:
- The developed SSNA platform offers a powerful approach for precise, on-demand, multiplexed gene silencing in cancer therapy.
- This technology integrates tumor-specific activation with dual-gene targeting, paving the way for advanced precision cancer treatments.
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