Click reactions are fast, chemoselective, and high-yielding covalent reactions between two reactive functions without generating armless byproducts.1 Such ideal reactions have found a wide range of applications2 in particular in the context of bioorthogonal chemistry.3 Although the number of click reactions available has considerably grown over the past twenty years, the toolbox continues to rise and improvements are still required to achieve compatible reactions in a biological environment. The sulfo-click reaction is an emergent surrogate click reaction involving a thioacid that reacts specifically with a sulfonyl azide leading to the formation of a N-acylsulfonamide linkage. The sulfo-click reaction fulfills the criteria of click reactions, generates only sulfur and dinitrogen as byproducts and is compatible with aqueous conditions. These characteristics are of particular interest in the field of nucleic acid chemistry. We recently developed the synthesis of original 4′-thioacid nucleoside analogues that opened the way to new interesting applications of the sulfo-click reaction. We will present our endeavor taking advantage of the biorthogonality of the sulfo-click reaction for bioconjugation.5 Indeed, a variety of sulfonyl azide derivatives were successfully conjugated to 4’-thioacid nucleosides under aqueous biocompatible conditions. Then, the interesting properties of the N-acylsulfonamide linkage in the field of medicinal chemistry6 were exploited to synthesize new cyclic dinucleotides for potential therapeutic applications by activating the native immune response.