Modular Nucleic Acid-Based Construct for Delivery of Immunostimulatory Agonists and Oncogene-Silencing Oligonucleotides in Tumours
Researchers have developed a multifunctional construct that assembles circular nucleic acids for targeted delivery, enabling co-delivery of immunostimulatory agonists and cytotoxins to remodel the tumour microenvironment
Systemic delivery of nucleic acid therapeutics to tissues outside the liver remains difficult due to rapid clearance, off-target accumulation, and inefficient cellular uptake. The authors 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. The 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.