Ionic liquid-caged nucleic acids enable active folding-based molecular recognition with hydrolysis resistance

Beyond storage and transmission of genetic information in cellular life, nucleic acids can perform diverse interesting functions, including specific target recognition and biochemical reaction acceleration; the versatile biopolymers, however, are acutely vulnerable to hydrolysis-driven degradation. Here, we demonstrate that the cage effect of choline dihydrogen phosphate permits active folding of nucleic acids like water, but prevents their phosphodiester hydrolysis unlike water. The choline-based ionic liquid not only serves as a universal inhibitor of nucleases, exceptionally extending half-lives of nucleic acids up to 6 500 000 times, but highly useful tasks of nucleic acids (e.g. mRNA detection of molecular beacons, ligand recognition of aptamers, and transesterification reaction of ribozymes) can be also conducted with well-conserved affinities and specificities. As liberated from the function loss and degradation risk, the presence of undesired and unknown nucleases does not undermine desired molecular functions of nucleic acids without hydrolysis artifacts even in nuclease cocktails and human saliva. Graphical Abstract