The role of siRNA and Argonaute 2 in Cancer Therapy: Molecular mechanisms and drug design perspectives

RNA interference (RNAi) has emerged as one of the key mechanisms of post-transcriptional gene regulation and one of the most promising therapeutic approaches for precision cancer therapy. These include small interfering RNAs (siRNAs) and the catalytic Argonaute 2 (Ago2) protein acting alone or jointly to silence target mRNAs in a sequence-specific way by an irreversible mechanism reminiscent of enzymatic degradation. This study reviews the structural and functional facets of siRNAs and Ago2, along with their synergistic role in targeted cancer gene silencing. We point out the therapeutic use of siRNA-directed oncogene (KRAS, MYC, BCL-2) silencing and explain how Ago2 participates in oncogenic signaling pathways such as MAPK/ERK, PI3K/AKT, and FAK. The chemical modification and nanocarrier-based delivery systems have got siRNA much more stable, specific, and bioavailable, thus virtually solving the major problems of translational research such as nuclease degradation and immune activation. The coupling of artificial intelligence, bioinformatics, and CRISPR technologies has profoundly changed the conception and accuracy of RNAi-based therapeutics. Delivery obstacles, immunogenicity, and large-scale manufacturing problems still exist, but recent inventions like self-delivering siRNAs, circular siRNAs, and hybrid CRISPR-RNAi systems are opening up the way to siRNA-Ago2 clinical applications at a fast pace. Altogether, these breakthroughs make RNAi a revolutionary route in molecularly targeted cancer therapy.