RNA guanine (G)-quadruplexes (rG4) are unique noncanonical structures composed of stacked guanine quadruplexes that play diverse roles in regulating gene expression, from transcription to protein synthesis. This study proposes a new splice-switching therapy using G-quadruplex-inducing antisense oligonucleotides (G-ASOs) to reinstate dystrophin expression in Duchenne muscular dystrophy (DMD) models. G-ASOs consist of two functionally independent domains that enable the formation of RNA/DNA hetero-G-quadruplex (hG4) structures. The antisense domain binds to complementary sequences within the target RNA, while the G-rich domain, which contains a sequence of continuous guanines (G-tract), interacts with the G-rich region of target RNA to form an hG4 structure. This precise binding forms an hG4 structure that effectively interrupts alternative splicing. In contrast to the traditional methods that block sterically, this technique employs steric hindrance by forming hG4 structures. Significantly, our findings show that hG4 structures can still form effectively even when the G-rich region of the target RNA and the antisense sequence are as much as 70 nucleotides apart. To address the challenges associated with G-quadruplex formation via G-ASO self-assembly, we developed bulge-containing G-ASOs. This enhancement improves both the efficiency of hG4 formation and the induction of exon-skipping therapy. In summary, this study highlights the potential of G-ASOs in gene therapy, specifically DMD, and marks significant progress in the development of novel therapeutic strategies. These findings highlight the effectiveness of G-ASOs in exon-skipping therapy and demonstrate the advancements in RNA structural manipulation.