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Despite the promise of tumor starvation therapies, they are often associated with nonspecific and incomplete energy blockade. Here, a novel paradigm of starvation therapy is proposed to synergize the "Zn 2+ interference"-mediated glycolysis inhibition and Zn 2+ -activating GLUT1 (Glucose transporter 1) tumor specific depletion for systematic energy exhaustion. It is discovered that ZIF-8 (zinc imidazolate metal-organic frameworks ) can induce abrupt intracellular Zn 2+ elevation preferentially in melanoma cells, and then achieve effective glycolysis blockade through "Zn 2+ interference"-triggered decrease of NAD + and inactivation of GAPDH, making it a powerful tumor energy nanoinhibitor. Meanwhile, Zn 2+ -activating DNAzymes for specifically cleaving GLUT1 mRNA is designed. This DNAzyme can only be activated under intracellular Zn 2+ overloading, and then directionally cut off glucose supply, which further restrains the adaptive up-regulation of glycolytic flux after glycolysis inhibition in tumors. Afterward, DNAzymes are loaded in ZIF-8 concurrently tethered by hyaluronic acid (HA), constructing a "nanoenabled energy interrupter ". Such a rational design presents a preferential accumulation tendency to tumor sites due to the active CD44-targeting mechanisms, specifically achieves remarkable systematic energy exhaustion in melanoma cells, and affords 80.8% in tumor growth suppression without systemic toxicity in vivo. This work verifies a fascinating therapeutic platform enabling ion interference-inductive starvation strategy for effective tumor therapy., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)