A Nano‐Autophagy Inhibitor Triggering Reciprocal Feedback Control of Cholesterol Depletion for Solid Tumor Therapy

Abstract Solid tumors are characterized by enhanced metabolism of lipid, particularly cholesterol, inspiring the exploration of metabolic therapy through cholesterol oxidase (COD)‐mediated cholesterol deprivation. However, the therapeutic efficacy of COD is limited due to the hypoxic tumor microenvironment and the protective autophagy triggered by cholesterol deprivation. Herein, a combination therapy for metabolically treating solid tumors through COD in conjunction with molybdenum oxide nanodots (MONDs), which serve as both potent oxygen generators and autophagy inhibitors, is reported. MONDs convert H 2 O 2 (arising from COD‐mediated cholesterol oxidation) into O 2 , which is then recycled by COD to form reciprocal feedback for cholesterol depletion. Concurrently, MONDs can overcome autophagy‐induced therapeutic resistance frequently occurring in conventional nutrient deprivation therapy by activating AKT/mTOR pathway phosphorylation. Combination therapy in the xenograft model results in an ≈5‐fold increase in therapeutic efficiency as compared with COD treatment alone. This functionally cooperative metabolic coupling strategy holds great promise as a novel polytherapy approach that will benefit patients with solid tumors.