Symmetric and near-symmetric cyanine probes for G-quadruplexes: molecular recognition, signal transduction, and biological applications.
G-quadruplexes (G4s) are dynamic noncanonical nucleic-acid structures involved in genome maintenance, transcription, RNA metabolism, and mitochondrial function, and are implicated in disease-associated processes. Symmetric and near-symmetric cyanines are versatile platforms for G4 recognition because their polymethine length, terminal heterocycles, charge distribution, conformational freedom, and supramolecular organization can be systematically tuned within related scaffolds. This review discusses how these structural features control G4 recognition and optical signal transduction through terminal G-tetrad stacking, loop and groove contacts, restriction of molecular motion, and aggregate reorganization. We first summarize in vitro recognition, structural discrimination, and G4-mediated sensing, and then discuss DNA and RNA G4 imaging, G4-associated biological processes, and emerging in vivo applications. Particular attention is given to several distinctions that are essential for interpreting probe performance: binding affinity versus fluorescence activation, topology preference versus DNA/RNA selectivity, organelle accumulation versus molecular targeting, and imaging contrast versus biological validation. Overall, molecular symmetry is considered a tunable design variable rather than a direct predictor of performance. Future studies should emphasize matched structural series, reversible and minimally perturbing probes, optical readouts that are less dependent on probe concentration, clear separation of DNA and RNA contributions, and standardized validation across solution, cellular, and whole-organism studies.