Smart Nucleic Acids as Future Therapeutics

Nucleic acid therapeutics (NATs) hold promise in treating undruggable diseases and are recognized as the third major category of therapeutics in addition to small molecules and antibodies. Despite the milestones that NATs have made in clinical translation over the past decade, one important challenge pertains to increasing the specificity of this class of drugs. Activating NATs exclusively in disease-causing cells is highly desirable because it will safely broaden the application of NATs to a wider range of clinical indications. Smart NATs are triggered through a photo-uncaging reaction or a specific molecular input such as a transcript, protein, or small molecule, thus complementing the current strategy of targeting cells and tissues with receptor-specific ligands to enhance specificity. This review summarizes the programmable modalities that have been incorporated into NATs to build in responsive behaviors. We discuss the various inputs, transduction mechanisms, and output response functions that have been demonstrated to date.