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Here, a synergistic strategy is established using an in\u2010house\u2010designed ionizable lipid nanoparticle (LNP) to co\u2010encapsulate VEGFA\u2010targeting 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\u2010derived and patient\u2010derived xenograft tumor models, iVG128 shows potent antitumor activity, achieving 2.6\u2010fold higher efficacy than Sorafenib, significantly prolonging survival. Untargeted metabolomics indicates that iVG128 eliminates the glutamine\u2010driven 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\u2010delivering enzymatic and RNA therapeutics, offering an effective strategy for cancer treatment through energy source depletion.<\/jats:p>","DOI":"10.1002\/advs.202519290","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T19:32:27Z","timestamp":1775763147000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combating VEGFA\u2010siRNA\u2010Induced Metabolic Reprogramming via Glucose Utilization Deprivation"],"prefix":"10.1002","volume":"13","author":[{"given":"Lulu","family":"Zheng","sequence":"first","affiliation":[{"name":"School of Life Science School of Interdisciplinary Science Key Laboratory of Molecular Medicine and Biotherapy Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering Beijing Institute of Technology Beijing 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