Challenges and advances for metabolically stabilizing siRNA
The therapeutic potential of small interfering RNA (siRNA) has been increasingly realized, yet metabolic stabilization remains a central effort to further extend clinical applications and durability of the siRNA drugs. This Expert Insight discusses key considerations for designing metabolic stabilization for siRNA scaffolds, with a focus on understanding degradation mechanisms across biological environments. We examine how nuclease susceptibility, chemical modification patterns, and tissue‑specific factors influence siRNA stability and efficacy. Particular attention is given to maintaining compatibility with Argonaute 2 (AGO2)-mediated RNA interference, as excessive and/or inappropriate positioning of chemical modifications compromises target engagement, RNA‑AGO2 interaction, and thus silencing efficiency. Clinically used and recently advanced chemical modifications are highlighted. Collectively, these insights aim to guide the rational design of next‑generation siRNA therapeutics with improved metabolic stability and clinical performance.