Nucleoside drives the self-assembly and enables delivery of phosphate containing therapeutics.

Nucleobase driven molecular recognition has enabled the self-assembly of a wide range of nucleosides and nucleotides. Emerging evidence suggests that ribose actively influences the nucleoside self-assembly process; however, how ribose associated chemical features contribute to this process remains unclear. Here, we propose a previously underexplored nucleoside phosphate recognition model in which the ribose 5'-OH group likely participates in hydrogen bonding with phosphate moieties, assisted by electrostatic pre-organization through protonation deprotonation equilibria. This model describes a site specific and reversible recognition mode that operates outside canonical base pairing within the systems examined. As a proof of concept, we systematically examined a series of phosphate-containing molecules, including nucleoside monophosphates, non-nucleosidic phosphate esters, and nucleoside analog drugs. Isoguanosine (isoG), adenosine (A), and guanosine (G) formed stable supramolecular assemblies with these phosphate containing molecules in aqueous solution, supporting the extendability of this assembly strategy across the tested systems. In particular, isoG organized nucleoside analog drugs and oligonucleotide RNAs into stable yet dynamic supramolecular complexes without chemical modification. These assemblies improved the biological activity and stability of phosphate containing nucleoside analogues, and provided preliminary evidence for oligonucleotide based applications. Together, these findings support a plausible nucleoside phosphate recognition model and provide a modular supramolecular strategy for constructing carrier free nucleoside based nanomaterials.