The data indicate that uncompensated mitochondrial proton leak is an important mechanistic contributor to the anesthetic response in addition to electron transport inhibition. These findings advance the authors' understanding of how anesthetics induce hypnosis and lay the foundation for next-generation drug discovery.

DNA-encoded library (DEL) technology is a powerful tool for discovering potent ligands for biological targets but constrained by limitations, including the insolubility of DNA in organic solvents and its instability under various reaction conditions, which restrict the reactivity scope and structural diversity achievable in library synthesis. Here, we present a new strategy called nanoDEL, where library molecules and DNA tags are displayed on the surface of nanoparticles. Since nanoparticles disperse well in both organic solvents and aqueous solutions, DEL synthesis can be accomplished using well-established organic solvent-based conditions, eliminating the need for aqueous conditions. Moreover, nanoDEL enables air-sensitive reactions that are inaccessible with conventional DEL methods relying on aqueous conditions. Notably, in nanoDEL, multiple copies of a DNA tag are attached to an individual nanoparticle to encode a single compound, significantly enhancing tolerance to DNA-damaging conditions. Even when most DNA tags are damaged, sequence analysis remains feasible via amplification of intact tags. Consequently, nanoDEL facilitates the convenient use of existing organic reactions without the necessity to develop DNA-compatible reactions. The potential of nanoDEL was validated by affinity selection against streptavidin as a model system and successfully applied to the discovery of potent small-molecule inhibitors for a kinase and stapled peptide inhibitors targeting a protein-protein interaction, exhibiting dissociation constants in the nanomolar range. Furthermore, we demonstrated that a large combinatorial library can be efficiently synthesized on nanoparticles using a synthetic scheme including moisture-sensitive reaction steps, which are not feasible with conventional DELs.