Antisense Versus Antigene in the Computer-Aided Design of Triplex-Forming Oligonucleotides (TFO): Insights from a Dual-Method Review, Combining Bibliometric and Systematic Review

This study offers a comprehensive overview of the scientific landscape surrounding computer-aided drug design (CADD) for triplex-forming oligonucleotides (TFOs) within antisense and antigene therapeutic strategies. A dual-method approach was used, combining bibliometric mapping of 6154 Scopus-indexed articles (1980-2023) to identify publication trends and intellectual networks, with a PRISMA 2020-guided systematic review of 62 experimental studies (2015-2024) from Scopus and Web of Science, after removing duplicates using AteneaSIRES. Results show the strong dominance and clinical maturity of antisense strategies, supported by 18 FDA/EMA/MHLW-approved drugs, whereas antigene approaches remain technically limited and underdeveloped. Antigene research has focused on triplex stability modeling and biophysical feasibility but faces challenges with poor biochemical stability, limited in vivo validation, and outdated methods. Meanwhile, antisense design benefits advanced CADD pipelines, including molecular dynamics and docking modeling. Based on these insights, we propose a practical, narrative roadmap as a methodological guide: integrating proven antisense design practices and providing actionable strategies to enhance antigene research, ultimately increasing the translational potential of therapeutic TFOs with solid mechanistic and translational support.