Hydrogen Sulfide‐Triggered Artificial DNAzyme Switches for Precise Manipulation of Cellular Functions

• Published in: Angewandte Chemie International Edition 2024-12, Vol.63 (49), p.e202410380-n/a
• Main Authors: Xie, Xuan, Nan, Hexin, Peng, Jialong, Zeng, Kaiqiang, Wang, Hong‐Hui, Huang, Yan, Nie, Zhou
• Format: Article
• Language: English
• Subjects: Allografts; Apoptosis; Apoptosis - drug effects; Artificial Receptor; Biological activity; Cell migration; Cell proliferation; Cell Proliferation - drug effects; Cell surface; Cell surface receptors; Cleavage; Deoxyribozymes; Dimerization; DNA, Catalytic - chemistry; DNA, Catalytic - metabolism; DNAzyme Engineering; DNAzyme Switches; Enzymatic activity; Functionals; Gas Signaling Molecule; Gene sequencing; Gene silencing; Humans; Hydrogen sulfide; Hydrogen Sulfide - chemistry; Hydrogen Sulfide - metabolism; Hydrogen Sulfide - pharmacology; mRNA; Nucleotide sequence; Phosphorothioate; Receptors; Switches
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202410380

The development of synthetic molecular tools responsive to biological cues is crucial for advancing targeted cellular regulation. A significant challenge is the regulation of cellular processes in response to gaseous signaling molecules such as hydrogen sulfide (H2S). To address this, we present the design of Gas signaling molecule‐Responsive Artificial DNAzyme‐based Switches (GRAS) to manipulate cellular functions via H2S‐sensitive synthetic DNAzymes. By incorporating stimuli‐responsive moieties to the phosphorothioate backbone, DNAzymes are strategically designed with H2S‐responsive azide groups at cofactor binding locations within the catalytic core region. These modifications enable their activation through H2S‐reducing decaging, thereby initiating substrate cleavage activity. Our approach allows for the flexible customization of various DNAzymes to regulate distinct cellular processes in diverse scenarios. Intracellularly, the enzymatic activity of GRAS promotes H2S‐induced cleavage of specific mRNA sequences, enabling targeted gene silencing and inducing apoptosis in cancer cells. Moreover, integrating GRAS with dynamic DNA assembly allows for grafting these functional switches onto cell surface receptors, facilitating H2S‐triggered receptor dimerization. This extracellular activation transmits signals intracellularly to regulate cellular behaviors such as migration and proliferation. Collectively, synthetic switches are capable of rewiring cellular functions in response to gaseous cues, offering a promising avenue for advanced targeted cellular engineering. Gas signaling molecule‐responsive artificial DNAzyme‐based switches (GRAS) have been developed as H2S‐driven nanodevices for manipulating cellular functions. GRAS is highly programmable and versatile, enabling the customization of user‐defined H2S signaling inputs to down‐regulate mRNA expression and activate RTK signaling pathways at various subcellular levels, thereby allowing for precise regulation of cell behavior.