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

Abstract

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.