Mitochondrial‐Cytosolic Cascade Metabolic Regulation System: A Robust Strategy to Disrupt Multipath Energy Replenishment in Cancer Therapy

Abstract Manipulating metabolic rewiring in cancer cells has become a central focus in cancer treatment. However, the intricate, yet not fully elucidated, adaptability of cancer metabolism frequently undermines the effectiveness of such interventions. Here, a novel cascade metabolic regulation system is presented by manipulating the mitochondria‐cytosol metabolic networks to disrupt multipath energy replenishment in cancer. Specifically, multienzymatic Mn‐LDH nanodiscs are synthesized, which not only impair energy metabolism in mitochondria by triggering mitochondrial dysfunction via self‐cascade catalysis, but also show the activity of blocking the compensatory energy metabolism from cellular glycogen. Concurrently, vessel embolization is combined to obstruct the carbon sources essential for both glycolysis in cytosol and the tricarboxylic acid (TCA) cycle in mitochondria, while simultaneously fostering an environment conducive to Mn‐LDH catalysis. This dual‐pronged regulation strategy induced ATP exhaustion and apoptosis in cancer cells, leading to remarkably enhanced antitumor efficacy in orthotopic liver tumor rabbit models compared to a standard clinical embolization formulation for advanced liver tumors. Moreover, comprehensive mechanism studies across cellular and animal models confirmed that this strategy effectively blocked multifaceted metabolic adaptations within the mitochondria and cytosol of cancer cells. Overall, this work offers a promising platform for metabolic intervention and provides important insights into cancer biology and management.