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

Area of Science:

• Biomedical Engineering
• Cancer Therapeutics
• Nanomedicine

Background:

• Vascular endothelial growth factor (VEGF) inhibitors are limited by tumor adaptation through tricarboxylic acid (TCA) cycle restoration and increased glycolysis.
• Targeting tumor energy metabolism presents a promising strategy to overcome resistance to anti-VEGF therapies.

Purpose of the Study:

• To develop a synergistic nanotherapeutic strategy for cancer treatment by co-delivering VEGFA-targeting siRNA and glucose oxidase.
• To enhance the efficacy of siRNA-based cancer therapy by simultaneously depleting both aerobic and anaerobic glucose utilization.

Main Methods:

• Design and synthesis of an ionizable lipid nanoparticle (LNP) for co-encapsulation of siVEGFA and glucose oxidase (GOx).
• In vitro evaluation of the LNP formulation (iVG128) on cellular energy production, angiogenesis, and mitochondrial function.
• In vivo assessment of iVG128's antitumor activity in CT26 and patient-derived xenograft models using metabolomics and transcriptomics.

Main Results:

• The optimal formulation, iVG128, effectively inhibited cellular energy production, suppressed microvessel formation, and induced persistent TCA cycle suppression.
• iVG128 demonstrated superior antitumor efficacy (2.6-fold higher than Sorafenib) and significantly prolonged survival in preclinical tumor models.
• Metabolomic and transcriptomic analyses revealed that iVG128 counteracted VEGF inhibition-induced metabolic compensation, enhanced apoptosis, and suppressed adaptive gene programs.

Conclusions:

• iVG128 represents a versatile nanoplatform for co-delivering enzymatic and RNA therapeutics.
• This strategy offers an effective approach for cancer treatment by comprehensively depleting tumor energy sources.
• The developed nanoplatform holds potential for overcoming therapeutic resistance in cancer by targeting metabolic vulnerabilities.