Organic reactions with DNA-conjugated substrates are important in technologies such as DNA-encoded libraries (DEL). One major challenge to the translation of many organic reactions to DNA-tagged substrates is the lack of solubility of the highly charged DNA oligomer in most organic solvents. A neutral acrylate block copolymer tightly interacted with DNA oligomers in their ammonium form, and solubilized them in pure apolar solvents such as dichloromethane, chloroform, toluene and many co-solvents of these. The DNA-polymer interaction in organic solvents led to formation of aggregates whose size correlated with DNA oligomer length. The copolymer solvent system was successfully exploited to diversify DNA-tagged substrates by isocyanide multicomponent reactions (IMCR) with broad scope and excellent yields for DNA-encoded library design. The DNA-solubilization method was applied in the synthesis of a macrocycle DEL using Ruthenium-promoted ring-closing metathesis as a key step.