Targeted HK2 Silencing via Folate‐Decorated Core–Shell Tecto‐Dendrimers Modulates Glycolysis‐Associated Metabolic Processes in Ovarian Cancer Cells

Ovarian cancer exhibits profound metabolic dependence on aerobic glycolysis, rendering hexokinase 2 (HK2), the rate‐limiting enzyme of this pathway, a key therapeutic vulnerability. However, therapeutic exploitation of HK2 silencing remains hindered by the intrinsic instability and inefficient intracellular delivery of siRNA. To overcome these limitations, we developed a folate‐functionalized core–shell tecto‐dendrimer (FA‐G5/G3) capable of selectively targeting HK2 through folate receptor‐mediated uptake and intracellular delivery of HK2 siRNA. The engineered nanocomplex exhibited favorable physicochemical properties, including stable architecture, appropriate particle size, and excellent biocompatibility. Following cellular internalization, FA‐G5/G3 facilitated intracellular delivery of HK2 siRNA, resulting in effective post‐transcriptional silencing of HK2 expression. This intervention disrupted glycolytic metabolism, reduced downstream LDHA expression, and markedly decreased extracellular lactate production. By suppressing a central glycolytic regulator, the FA‐G5/G3‐mediated HK2 silencing strategy reduced glycolytic activity and provided a potential approach for exploiting metabolic vulnerabilities in ovarian cancer. Collectively, this study establishes a targeted CSTD‐based siRNA delivery platform for glycolysis‐associated metabolic changes and provides a promising therapeutic strategy for overcoming metabolic vulnerabilities in ovarian cancer.