Supplementary file 1_Long-acting RNAi therapeutics in hypertension: limitations of single-target AGT silencing and rational multi-target synergistic strategies.pdf

Existing reviews have largely summarized AGT-targeted RNA interference (RNAi) therapeutics. Rather than cataloguing individual agents, we propose a phenotype-matched framework that uses disease mechanisms to guide target selection, delivery strategies, and translational development toward precision RNAi therapy for hypertension. We review current clinical progress, examine the mechanistic basis of multi-pathway blockade, and discuss emerging molecular scaffolds for dual- and multi-target siRNA therapeutics.

Finally, we discuss the major barriers to clinical translation—including extrahepatic delivery, pharmacological reversibility, and safety considerations—and identify the advances required for phenotype-guided RNAi therapies to move toward precision cardiovascular medicine. We emphasize that this phenotype-matched model is intended to generate hypotheses for target prioritization and validation, and does not represent a clinically established treatment strategy.</p>