Triple-Targeted DNA Nanozyme Executes Disulfidptosis for Glioma Elimination.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Targeting mitochondrial dysfunction is a key strategy for glioma therapy.
• Inducing specific cell death pathways using non-genetic nanotherapeutics for glioma is challenging.

Purpose of the Study:

• To develop a triple-targeted DNA nanozyme for precise glioma cell death induction.
• To investigate the mechanism of disulfidptosis activation by the nanozyme.

Main Methods:

• Constructed a programmable nanoplatform (TMGH@AD) using rolling circle amplification.
• Integrated targeting ligands for BBB penetration, tumor accumulation, and mitochondrial localization.
• Incorporated a G4/Hemin DNAzyme and Alexidine (AD) for synergistic ROS generation and mitochondrial disruption.

Main Results:

• TMGH@AD achieved sequential delivery to brain tumors and accurate mitochondrial localization.
• The DNAzyme catalyzed hydroxyl radical generation, causing a synergistic ROS burst with AD.
• This cascade triggered PTPMT1 dysregulation, oxidative stress, NADPH depletion, and disulfide accumulation, inducing disulfidptosis.

Conclusions:

• Developed a novel DNA nanozyme strategy combining targeted delivery and disulfidptosis activation.
• Overcame delivery barriers and exploited metabolic vulnerabilities for glioma treatment.
• TMGH@AD offers a promising therapeutic approach for glioma eradication.