DNA-encoded libraries are collections of small molecules covalently bound to single or double-stranded oligonucleotides, which sequences individually carry encoded information about the identity of the molecule. These oligonucleotide conjugates are assembled using building blocks or cores, and their corresponding encoding DNA tags. Libraries, once synthesized, can be screened towards biological targets of interest, and binders, being physically separated from non-binders, can be identified simple decoding of the unique DNA tags, using PCR amplification and DNA sequencing. Ever since the conceptual inception of DNA-encoded library technology in 1992, [1] and following applicative studies, [2, 3] the field has been rapidly emerging as a powerful pathway to discover valuable chemical matter for drug discovery and probe molecules. Thanks to the efforts of many academics and industrial groups, this technology has been continuously evolving and benefited from the multidimensional advancements: new on-DNA chemical reactions, improved selection methods, increasingly affordable nucleotide sequencing, and ameliorated data analysis approach to reveal the enriched binders. [4, 5] The significance and strong impact of DELT in unveiling relevant hits in an efficient and economical manner was recently witnessed by the expedient access to SARS-CoV-2 Mpro inhibitors, [6] and naturally became increasingly significant in drug discovery. These efforts notably contributed to the discovery of two phase 2 clinical candidates GSK2256294 and GSK2982772 from GSK and recently FDA-approved X-165 for Phase I clinical trials