G-quadruplexes (G4) are noncanonical nucleic acid secondary structures formed by guanine-rich sequences that can form higher-order multimers under appropriate conditions and represent attractive targets for multivalent molecular recognition. Here, we propose a rational ligand design strategy based on multivalency, in which ligand molecules are covalently linked into polymer-like macromolecules. Using coarse-grained molecular dynamics, we show that these “polyligands” intercalate G4 multimers more efficiently than their monomeric counterparts, achieving strong stabilization through cooperative effects, even when individual ligands exhibit low intrinsic binding affinity. Polyligand intercalation induces structural changes in G4 multimers, modifying their size and stiffness. Using a quantitative polymer theory framework, we connect these structural changes with the thermal stabilization of G4 multimers. Polyligands represent a general design principle for G4-targeting molecular stabilizers, offering enhanced G4 stabilization via programmable linker length and backbone rigidity.
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