This review presents recent advancements in light-mediated modifications of nucleic acids, with a particular focus on innate functionalization, interstrand crosslinking, photouncaging, photoswitching, and DNA-encoded libraries. These methodologies have demonstrated significant advantages over conventional metal-based or metal-free approaches, including crosscoupling strategy, offering promising pathways for innovative therapeutic drug discovery.

Chemical modification of nucleic acids (oligonucleotide, DNA, and RNA) is a powerful tool, widely used in chemical biology. There is a growing interest in light-mediated nucleic acid modification within biological systems, driven by the exceptional spatiotemporal precision that light offers. Moreover, light-induced chemical modification of nucleic acids, utilizing light as an external energy source, offers a powerful and efficient alternative to conventional labor-intensive de novo synthesis. In this regard, visible light exhibits a highly efficient and selective approach, enabling precise labeling of target sites without compromising their structural integrity, while high-energy UV light triggers detrimental photochemical reactions, causing DNA/RNA damage. Light-mediated selective labeling and interstrand crosslinking of DNA/RNA duplexes hold great potential for applications in DNA repair, gene regulation, and nanotechnology. Photouncaging and photoswitching enable precise control over biological processes like transcription, RNA interference, and translation. Moreover, light-mediated DNA-encoded libraries provide a sustainable and efficient method for generating vast small-molecule libraries, valuable for pharmaceutical discovery. This review highlights recent advancements in light-mediated nucleic acid modifications, including labeling, crosslinking, photouncaging, photoswitching, and DNA-encoded library synthesis, accompanied by comprehensive discussion and analysis.