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Mito-specific cascade amplifier sniping metabolism homeostasis for multimodal imaging-guided antitumor bioenergetic therapy

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Nano Research 2024年第11期17卷 9908-9919页

作者： Jingjing Yang Yuanlin Zhang Maoquan Chu Jin Qian Jie Liu Manyu Wang Zhe Qiang Jie Ren Institute of Nano and Biopolymeric Materials School of Materials Science and Engineering Tongji University Shanghai 201804 China Molecular Biomarkers Nano-Imaging Laboratory Brigham and Women’s Hospital and Department of Radiology Harvard Medical School Boston MA 02115 USA Research Center for Translational Medicine at Shanghai East Hospital School of Life Science and Technology Tongji University Shanghai 20092 China 118 College Dr School of Polymer Science and Engineering The University of Southern Mississippi Hattiesburg MS 39406 USA

Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by providing NAD+ precursors and/or intermediates, thus promoting their survival rate and potentially driving uncontrollable proliferation. Here, a synergistic intervention NAD+/NADH homeostasis and mitochondrial metabolism strategy with magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) are developed to address grand challenge of metabolic reprogramming for antitumor bioenergetic therapy. A mitochondrial-targeted cascade amplification nanoplatform ([β-MQ]TRL), triggered by NAD(P)H: quinone oxidoreductase-1 (NQO1), can enable a continuous depletion of cytosol NADH until cell death. The end-product, hydrogen peroxide (H_(2)O_(2)), can be further catalytically converted to higher toxic ·OH in proximity to mitochondria based on [β-MQ]TRL mediated Fenton-like reaction, hijacking tumorigenic energy sources and leading to mitochondrial dysfunction. Additionally, the mild thermal ablation enabled by [β-MQ]TRL further amplifies this cascade reaction to effectively prevent tumor metastasis and recurrence. This synchronous intervention strategy with MRI/PAI establishes unprecedented efficiency in antitumor bioenergetic therapy in vivo, which shows excellent promise for clinical application.

关键词： metabolism programming nicotinamide adenine dinucleotide(NAD+/NADH)pools homeostasis disruption mitochondrial-targeting cascade therapy magnetic resonance imaging(MRI)/photoacoustic imaging(PAI)

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