Special issue on “Metal complexes targeting non-canonical nucleic acid structures”

Non-canonical nucleic acid structures are increasingly recognised as functionally relevant elements within the genome, emerging as key regulators in processes that extend well beyond the classical paradigm of B-form DNA. Over the past decade, a growing body of evidence has demonstrated that secondary structures such as G-quadruplexes (G4s), i- motifs, triplexes, quadruplex–duplex hybrids, mismatches and other locally distorted motifs arise in a sequence- and context-dependent manner, responding dynamically to changes in supercoiling, transcriptional activity, ionic environment and cellular stress. These structures are now known to populate promoter regions of oncogenes, telomeric ends, untranslated regions of mRNAs and sites of DNA repair, where they influence gene expression, replication timing, chromatin organisation and genome stability. Their functional relevance, ranging from transcriptional regulation to the maintenance of chromosome integrity, has made them attractive targets for chemical interrogation and therapeutic modulation. A central challenge in this field lies in achieving selective recognition across such a heterogeneous landscape of folds and microenvironments. Transition-metal complexes, thanks to their well-defined coordination geometries, tuneable ligand environments, accessible redox properties and favourable electrostatic and π-stacking interactions, offer a particularly versatile platform to address this challenge. Their modularity enables precise control over size, planarity, charge and hydrogen- bonding capability, allowing them to discriminate among different topologies and to stabilise or remodel DNA structures in ways that purely organic molecules often cannot. As a result, metal complexes have become indispensable tools for probing the structural diversity of nucleic acids, acting as conformation-selective binders, luminescent reporters, photoreactive agents or therapeutic candidates. The contributions collected in this Special Issue illustrate how metal complexes interact with structurally diverse nucleic acid motifs and highlight emerging strategies for targeting their unique features, spanning systems that engage well-folded G-quadruplexes, hybrid junctions between folded and duplex regions, mismatch-containing helices and therapeutically relevant metal complexes whose activity extends into the realm of non-canonical DNA recognition.