Recent Advances and Future Directions in On-DNA Reaction Development.

DNA-encoded library (DEL) technology has emerged as a powerful platform for small-molecule discovery, in which on-DNA reaction development plays a central role in determining accessible chemical space. Early on-DNA chemistry mainly focused on establishing robust DNA-compatible transformations under mild aqueous conditions but often generated structurally limited libraries. Recent advances in photochemistry, electrochemistry, biocatalysis, and complexity-generating reactions have substantially expanded the scope of accessible on-DNA transformations and enabled the incorporation of increasingly diverse and medicinally relevant scaffolds into DELs. In this Viewpoint, we discuss the recent progress and emerging trends in on-DNA reaction development, with particular emphasis on the transition from compatibility-driven chemistry toward function-oriented DEL synthesis. We further highlight current challenges and future opportunities for developing precision on-DNA chemistry to support next-generation ligand discovery.