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Research Article

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

Jingjing Yang1, Yuanlin Zhang2, Maoquan Chu3, Jin Qian4, Jie Liu3, Manyu Wang3, Zhe Qiang4( ), Jie Ren1( )
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
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Graphical Abstract

A mitochondrial-specific cascade generator enables synchronous disruption of nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis and mitochondrial metabolism for magnetic resonance/photoacoustic (MR/PA) imaging-guided antitumor bioenergetic therapy.

Abstract

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 (H2O2), 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.

Keywords

metabolism programmingnicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis disruptionmitochondrial-targeting cascade therapymagnetic resonance imaging (MRI)/photoacoustic imaging (PAI)

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Nano Research
Volume 17 Issue 11,
November 2024
Pages 9908-9919
DOI: 10.1007/s12274-024-6892-y
Cite this article:
Yang J, Zhang Y, Chu M, et al. Mito-specific cascade amplifier sniping metabolism homeostasis for multimodal imaging-guided antitumor bioenergetic therapy. Nano Research, 2024, 17(11): 9908-9919. https://doi.org/10.1007/s12274-024-6892-y
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Received: 19 May 2024
Revised: 09 July 2024
Accepted: 15 July 2024
Published: 16 August 2024
© Tsinghua University Press 2024
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