Mitochondria-Targeted Chemodynamic Nanoagent Synergizes With Transcriptional Modulation for Enhanced Pyroptosis...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Pyroptosis is an immunogenic cell death pathway mediated by gasdermin E (GSDME).
• Chemodynamic therapy (CDT) can induce pyroptosis, but epigenetic silencing of GSDME in tumors limits its efficacy.
• Tumor cells often undergo apoptosis, an immunologically silent cell death, instead of pyroptosis.

Purpose of the Study:

• To develop a mitochondria-targeted CDT agent for enhanced pyroptosis immunotherapy.
• To overcome the epigenetic silencing of GSDME in cancer cells.
• To create a strategy for stimulating systemic antitumor immune responses.

Main Methods:

• Development of mitochondria-targeted nanoparticles (Mito-CA/TA NPs) encapsulating chloranil (CA) and triamcinolone acetonide (TA).
• Utilizing CA for chemodynamic conversion of hydrogen peroxide (H2O2) to hydroxyl radicals (•OH) within mitochondria.
• Employing TA to reverse GSDME epigenetic silencing and promote GSDME cleavage.
• Integrating chemiluminescent functionality for real-time monitoring of •OH generation.

Main Results:

• Mito-CA/TA NPs effectively generated hydroxyl radicals in mitochondria at physiological pH.
• TA release reversed GSDME downregulation, restoring pyroptosis.
• In situ •OH generation disrupted mitochondrial integrity, activating caspase-3 and GSDME cleavage.
• The agent triggered pyroptosis and stimulated systemic antitumor immune responses.

Conclusions:

• Mito-CA/TA NPs represent a potent strategy for enhancing pyroptosis-based cancer immunotherapy.
• The developed agent overcomes GSDME epigenetic silencing, promoting immunogenic cell death.
• This approach offers a universal method to improve antitumor immunity via pyroptosis induction.