Ultrasound-Driven Interfacial Electron Modulation Reprograms Mitochondrial Metabolism for Glioblastoma Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Glioblastoma (GBM) treatment is hindered by the blood-brain barrier (BBB), hypoxic tumor environments, and metabolic adaptability.
• Targeting mitochondrial metabolism in GBM is difficult due to its essential role in normal brain cells and limitations of current therapies.

Purpose of the Study:

• To develop an ultrasound-responsive nanoplatform for targeted GBM therapy.
• To investigate the potential of controlled carbon monoxide (CO) generation to disrupt GBM mitochondrial metabolism and induce cell death.

Main Methods:

• Assembly of Ni/LDH@M nanoplatform from nickel and layered double hydroxide nanosheets, cloaked with glioma cell membranes.
• Ultrasound irradiation to trigger CO generation from the nanoplatform.
• Evaluation of CO's effect on mitochondrial electron transport chain (ETC) and induction of apoptosis and immunogenic cell death (ICD) in GBM cells.
• In vivo testing in mice with orthotopic GL261 gliomas.

Main Results:

• The Ni/LDH@M nanoplatform demonstrated ultrasound responsiveness and targeted accumulation in orthotopic gliomas.
• Ultrasound-activated CO generation effectively inhibited mitochondrial cytochrome c oxidase and disrupted ETC function.
• The treatment induced mitochondria-dependent apoptosis and immunogenic cell death (ICD) in GBM cells.
• Ultrasound-activated Ni/LDH@M suppressed tumor progression and prolonged survival in mice.

Conclusions:

• Controlled CO generation via ultrasound-responsive nanoplatforms can reprogram tumor-cell mitochondrial metabolism for GBM therapy.
• The developed Ni/LDH@M nanoplatform shows promise as a novel therapeutic strategy for glioblastoma.