Modulating G-quadruplexes for therapeutic intervention: Structural diversity, stability, and emerging nucleic-acid-based strategies

G-quadruplexes (G4s) are non-canonical nucleic acid structures formed by guanine-rich DNA or RNA sequences. The G4s are formed by planar G-tetrads and stabilized by monovalent metal cations such as potassium or sodium. The structural diversity of G4s arises from differences in strand orientation, loop arrangement, and molecularity, leading to multiple topologies. The length of guanine tracts (G-tracts) and the number of strands involved further influence G4 folding, stability, and biological function. G-quadruplexes are commonly found in key genomic regions such as telomeres, promoters, and untranslated regions, where they play important roles in regulating fundamental biological processes, including replication, transcription, and translation. In this review, we summarize the molecular factors influencing G4 formation and stability. We also discuss recent advances in therapeutic strategies for targeting G-quadruplexes. Particular attention is given to antisense oligonucleotides (ASOs), ASO-ligand conjugates, peptide nucleic acids (PNAs), and PNA-conjugates as chemical tools for selective G4 recognition and modulation. We highlight the potential of nucleic-acid-based approaches for molecular therapeutics, including applications in anticancer and antiviral treatments.