A Smart Nano‐Theranostic Platform Based on Dual‐microRNAs Guided Self‐Feedback Tetrahedral Entropy‐Driven DNA Circuit

Abstract

MicroRNAs (miRNAs) can act as oncogenes or tumor suppressors, capable of up or down‐regulating gene expression during tumorigenesis; they are diagnostic biomarkers or therapeutic targets for tumors. To detect low abundance of intracellular oncogenic miRNAs (onco‐miRNAs) and realize synergistic gene therapy of onco‐miRNAs and tumor suppressors, a smart nano‐theranostic platform based on dual‐miRNAs guided self‐feedback tetrahedral entropy‐driven DNA circuit is created. The platform as a delivery vehicle is a DNA tetrahedral framework, in which the entropy‐driven DNA circuit achieves a dual‐miRNAs guided self‐feedback, between an in situ amplification of the onco‐miRNAs and activation of suppressor miRNAs release. To test this platform, dual‐miRNAs are selected, miRNA‐155, an up‐regulated miRNA, as cancer indicators, and miRNA‐122, a down‐regulated miRNA as therapy targets in hepatocellular carcinoma, respectively. Through the circuit, the platform to detect onco‐miRNAs at femtomolar level as well as visualized miRNAs inside cells, fixed tissues, and mice is programmed. Furthermore, triggered by miRNA‐155, preloaded miRNA‐122 is amplified via the self‐feedback and released into target cells; the sudden increase of miRNA‐122 and simultaneous decrease of miRNA‐155 synergistically served as therapeutic drugs for gene regulation with enhanced antitumor efficacy and superior biosafety. It is envisioned that this nano‐theranostic platform will initiate an essential step toward tumor theranostics in personalized/precise medicine.

DNA Logic Gates Integrated on DNA Substrates in Molecular Computing

“…However, integration of logic gates as circuits into a single substrate have not been used in an intracellular environment yet. Instead, our literature study has revealed two distinct architectural approaches: i) the integration of DNA logic gates within a single DNA substrate, where gate‐to‐gate communication occurred, is absent in vitro studies; [11,41,42,81–86] and ii) the interaction and regulatory behavior of DNA logic gates localized on separate substrates has been proposed [79,87] …”

“…Yang et al. proposed an entropy‐driven aggregation of DNA tetrahedron circuits that led to amplification of the output fluorescence signal and improved LOD from nM to fM range [79] . Therefore, further exploration of in vitro DNA ICs can be done using these 3D DNA substrates.…”

Integration of Isothermal Enzyme‐Free Nucleic Acid Circuits for High‐Performance Biosensing Applications

“…It also provides a facile and versatile strategy for the detection of other biomarkers in living cells. As shown in Figure 1D, [27] Yang et al established a smart nanoplatform based on a self-feedback tetrahedral entropy-driven DNA circuit guided by dual miRNAs. MiRNA-155 binds to sites 5* and 6* on the tetrahedron, allowing the W strand and miRNA-122 to be released from the tetrahedron and triggering the further entropy-driven reactions.…”

Scaling up of a Self‐Confined Catalytic Hybridization Circuit for Robust microRNA Imaging

“…The high predictability and hybridization fidelity of DNA makes it possible to design DNAbased circuits with emergent properties and functions. [25][26][27][28][29] There have been some explorations on the immobilization of circuit elements on DNA-encoded origami scaffolds, [30][31][32] dedicated to the orienting of multi-step reactions within a confined volume. Such circuitry written into DNA origami forms a benchmark for the construction of synthetic biocircuits.…”