Combating VEGFA‐siRNA‐Induced Metabolic Reprogramming via Glucose Utilization Deprivation

ABSTRACT Vascular endothelial growth factor (VEGF) inhibitors suppress tumor energy supply, but their efficacy is often limited by the restoration of tricarboxylic acid (TCA) cycle activity and enhanced glycolysis. Here, a synergistic strategy is established using an in‐house‐designed ionizable lipid nanoparticle (LNP) to co‐encapsulate VEGFA‐targeting siRNA (siVEGFA) and glucose oxidase (GOx), thereby enhancing siRNA efficacy by depleting both aerobic and anaerobic glucose utilization. At the cellular level, the optimal formulation, iVG128, inhibits energy production, suppresses microvessel formation, and induces mitochondrial ultrastructural changes, leading to persistent suppression of the TCA cycle. In both CT26 cell‐derived and patient‐derived xenograft tumor models, iVG128 shows potent antitumor activity, achieving 2.6‐fold higher efficacy than Sorafenib, significantly prolonging survival. Untargeted metabolomics indicates that iVG128 eliminates the glutamine‐driven compensation induced by VEGF inhibition, thereby exacerbating metabolic stress and promoting apoptosis. Transcriptomic profiling reveals that VEGFA silencing induces adaptive gene programs related to PDH inhibition, hypoxia signaling, and glutamine metabolism, and these responses are largely suppressed by iVG128. Collectively, iVG128 represents a versatile nanoplatform for co‐delivering enzymatic and RNA therapeutics, offering an effective strategy for cancer treatment through energy source depletion.