Mechanistic intracellular PK/PD modeling to inform development strategies for small interfering RNA therapeutics.

ABSTRACT: Small interfering RNA (siRNA) therapeutics provide a targeted approach to silence disease-related genes, with notable success in liver-targeting applications. However, the quantitative effects of siRNA properties, such as stability and affinity, as well as biological factors like cell proliferation, mRNA turnover, and abundance, on gene silencing, particularly for extrahepatic targets, remain poorly understood. To identify determinants influencing gene knockdown extent and duration, we developed a mechanistic intracellular pharmacokinetic/pharmacodynamic (PK/PD) model for RNAiMAX-delivered siRNA, based on cytoplasmic siRNA disposition, RISC-loaded siRNA exposure, and mRNA knockdown across different targets in MCF7 and BT474 cells. The model highlighted the critical roles of cell proliferat

SUBMITTER: Chen L 

PROVIDER: S-EPMC12002994 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature