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<p>Systemic delivery of nucleic acid therapeutics to tissues outside the liver remains difficult because of rapid clearance, off-target accumulation and inefficient cellular uptake. Here we developed a multifunctional construct that assembles circular nucleic acids for targeted delivery, termed circular functional molecular flare. These constructs are produced by ligase-mediated, DNA-templated polymerization: short codons encoding aptamers, oncogene-silencing oligonucleotides, CpG motifs and drug conjugates are hybridized onto circular templates and covalently linked to form stable structures with defined composition and valence. The resulting molecules enable co-delivery of immunostimulatory agonists and cytotoxins to remodel the tumour microenvironment and activate antigen-presenting cells, eliciting potent antitumour immune responses in mouse models. Aptamer–antisense chimeras achieve selective knockdown of the oncogenic Kirsten rat sarcoma viral oncogene homologue transcript in pancreatic cancer through RNase H-mediated degradation of its messenger RNA, suppressing tumour growth without transfection reagents. These findings establish circular functional molecular flare as a chemically programmable approach for engineering targeted nucleic acid therapeutics with improved stability, specificity and efficacy in extrahepatic disease models.</p>

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Modular nucleic acid-based construct for delivery of immunostimulatory agonists and oncogene-silencing oligonucleotides in tumours

  • 期刊论文

  • 发表日期：

    2026年6月3日

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  • Hongli Chi,
  • Keli An,
  • Jiaxuan He,
  • Yanlin Du,
  • Shijie Yang,
  • Yani Wang,
  • Xinni Liu,
  • Yan Li,
  • Mingbo Shu,
  • Mengjun Zheng,
  • Jinling Chen,
  • Shiqi Jiang,
  • Liangwei Lu,
  • Ting Fu,
  • Jingyi Chen,
  • Ming Cheng,
  • Penghui Zhang,
  • Weihong Tan

摘要

Systemic delivery of nucleic acid therapeutics to tissues outside the liver remains difficult because of rapid clearance, off-target accumulation and inefficient cellular uptake. Here we developed a multifunctional construct that assembles circular nucleic acids for targeted delivery, termed circular functional molecular flare. These constructs are produced by ligase-mediated, DNA-templated polymerization: short codons encoding aptamers, oncogene-silencing oligonucleotides, CpG motifs and drug conjugates are hybridized onto circular templates and covalently linked to form stable structures with defined composition and valence. The resulting molecules enable co-delivery of immunostimulatory agonists and cytotoxins to remodel the tumour microenvironment and activate antigen-presenting cells, eliciting potent antitumour immune responses in mouse models. Aptamer–antisense chimeras achieve selective knockdown of the oncogenic Kirsten rat sarcoma viral oncogene homologue transcript in pancreatic cancer through RNase H-mediated degradation of its messenger RNA, suppressing tumour growth without transfection reagents. These findings establish circular functional molecular flare as a chemically programmable approach for engineering targeted nucleic acid therapeutics with improved stability, specificity and efficacy in extrahepatic disease models.