Manipulating DNA and RNA structures via click-to-release caged nucleic acids for biological and biomedical applications.

Effectively controlling the structures of DNA and RNA is crucial for their functional utilization in material development, biological regulation, and medical applications. Here, we present a gain-of-function strategy for controlling DNA and RNA structures using an inverse electron-demand Diels-Alder (IEDDA) based click-to-release reaction. By incorporating click reaction-cleavable caged moiety into oligonucleotides, we disrupt activated base pairs, allowing controlled release of biofunctional higher-order nucleic acid structures. This click-to-release caged DNA was employed to control DNA duplex formation. Next, we demonstrated the utility of "click-to-release" strategy for regulated release of Z-DNA or Z-RNA and bind associated proteins. In addition, the approach was used to manipulated G-quadruplex formation in vitro and in vivo, enabling visual detection of G-quadruplex using BVE-caged DNA with fluorescent dye. Furthermore, we demonstrated the utility of click-to-release caged DNA for Quantum Dots (QDs) functionalization, enabling precise molecular imaging for cancer diagnosis. Finally, we developed a click-to-release controllable nucleic acid aptamer for precise blood clotting regulation and anticoagulation therapy. This strategy provides moderate kinetics, excellent orthogonality, and biocompatibility. It establishes a new pathway towards control of nucleic acid structures and functions, which has promising applications in various biological procedures and nucleic acid medicines.