Noble Metal Complexes and Non-Canonical Nucleic Acids: From G-Quadruplex Recognition to Emerging Functional Architectures

Non-canonical nucleic acid structures such as G-quadruplexes (G4s), i-motifs, triplexes, junctions, and structured RNA domains offer coordination environments that differ fundamentally from those of canonical duplex DNA. This review is deliberately G4-centred, because DNA G4s currently provide the most mature mechanistic and biological evidence for noble-metal recognition, while i-motifs, quadruplex–duplex hybrids, junctional structures, R-loops, Z-DNA/Z-RNA, and structured RNA remain emerging or less extensively validated target classes. The discussion addresses how platinum, gold, palladium, and silver complexes recognize these architectures through combinations of coordination chemistry, pi-stacking, electrostatics, scaffold-dependent shape complementarity, and metal-mediated base pairing. A further distinction is made between direct structural recognition, cellular target engagement, and downstream phenotypic responses, emphasizing where causality has been experimentally demonstrated and where it remains inferential. Particular emphasis is placed on G-quadruplexes in telomeric, promoter, and mitochondrial contexts, while i-motifs, junctional DNA, hybrid DNA/RNA structures, and structured RNA are treated as expanding but less mature areas of investigation. The review also critically addresses selectivity, resistance, delivery, and translational challenges, highlighting how the concept of functional architectures can help unify structural chemistry with pathway-level biology in the design of next-generation metallodrugs.