Lighting up three-dimensional nanolantern for circular RNA imaging and precise gene therapy

Abstract

Circular RNAs (circRNAs) are a category of endogenous single-stranded RNAs with covalently closed head-to-tail topology, and they play a crucial part in regulating gene expression at post-transcriptional and transcriptional levels. Herein, we construct a three-dimensional nanolantern for circRNA imaging and precise gene therapy. This assay involves an integrated multi-functionalized lantern-shaped probe. By rationally engineering four vertexes and six edges of DNA dimensional architecture, the integrated nanolantern probe functions not only as a delivery machine for reactants but also as a scaffold for catalytic hybridization reactions. The presence of circCDYL initiates the entropy-driven strand displacement assembly of nanolantern monomer to generate long nanolantern concatemers while releasing small interfering RNAs (siRNAs) for target-stimulated on-site and on-demand gene therapy. Compared with canonical linear probe-based catalytic circuit, this method exhibits significantly improved fluorescence stability and gene therapy efficiency due to the inherent resistance of DNA rigid structure to enzymic digestion. This strategy enables one-step detection of circCDYL with a limit of detection (LOD) of 28.2 aM, and accurate quantification of circCDYL expressions in breast cancer patients and healthy individuals. Importantly, this catalytic circuit can achieve tumor-specific gene silencing with minimal off-target toxicity, holding great potential in tumor diagnosis and precise medicine.