Nano‐enabled Tumor Systematic Energy Exhaustion via Zinc (II) Interference Mediated Glycolysis Inhibition and Specific GLUT1 Depletion

• Published in: Advanced science Vol. 9; no. 7; pp. e2103534 - n/a
• Main Authors: Wu, Sixuan, Zhang, Kaixiang, Liang, Yan, Wei, Yongbin, An, Jingyi, Wang, Yifei, Yang, Jiali, Zhang, Hongling, Zhang, Zhenzhong, Liu, Junjie, Shi, Jinjin
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.03.2022; John Wiley and Sons Inc; Wiley
• Subjects: Blood vessels; Cell growth; Energy; Energy Metabolism - drug effects; Gene expression; Glucose; Glucose - metabolism; Glucose Transporter Type 1 - antagonists & inhibitors; Glucose Transporter Type 1 - genetics; GLUT1 depletion; Glycolysis - drug effects; glycolysis inhibition; Humans; Hyaluronic acid; Metabolism; Nanoparticles; Nanoparticles - therapeutic use; Neoplasms - drug therapy; starvation therapy; systematic energy exhaustion; Tumors; Zinc; zinc (II) interference; Zinc - metabolism; zinc (II) interference; glycolysis inhibition; GLUT1 depletion; starvation therapy; systematic energy exhaustion
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202103534

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 “Zn2+ interference”‐mediated glycolysis inhibition and Zn2+‐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 Zn2+ elevation preferentially in melanoma cells, and then achieve effective glycolysis blockade through “Zn2+ interference”‐triggered decrease of NAD+ and inactivation of GAPDH, making it a powerful tumor energy nanoinhibitor. Meanwhile, Zn2+‐activating DNAzymes for specifically cleaving GLUT1 mRNA is designed. This DNAzyme can only be activated under intracellular Zn2+ 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. A “nano‐enabled energy interrupter” with capability of specific Zn(II) homeostasis disrupting in malignant melanoma is designed. The specific Zn(II) overloading in tumor cells can inhibit glycolysis and initiate GLUT1 depletion for energy exhaustion induced tumor therapy, while the “nanoenabled energy interrupter” has negligible impact on Zn(II) homeostasis and energy metabolism in normal cells.