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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
PubMed

Insights

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.
Keywords:
gene‐targeted therapymultiplexed gene silencingon‐demand activationsuperspherical nucleic acid

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