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Mitochondria-Targeted Photodynamic Agents Drive Robust Pyroptosis by Caspase-3/GSDME Activation and Cardiolipin
Dongsheng Zhang1, Xueli Zhang1, Mengyuan Huang1
1School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, People's Republic of China.
Angewandte Chemie (International Ed. in English)
|May 29, 2026
Summary
Researchers developed novel mitochondria-targeted photosensitizers that trigger pyroptosis, a programmed cell death, for cancer therapy. These agents effectively induce cancer cell death and show promise in preclinical models.
Area of Science:
- Biochemistry
- Materials Science
- Oncology
Background:
- Photodynamic therapy (PDT) is a promising cancer treatment, but efficiently inducing pyroptosis, a specific cell death pathway, requires optimized photosensitizers (PSs).
- Developing PSs that target mitochondria and trigger pyroptosis is crucial for enhancing PDT efficacy.
Purpose of the Study:
- To design and synthesize novel mitochondria-targeted supramolecular photosensitizers (PSs) for effective PDT-induced pyroptosis.
- To investigate the mechanism of PS-induced pyroptosis, focusing on caspase-3/gasdermin E (GSDME) activation and cardiolipin (CL) externalization.
Main Methods:
- Rational design and synthesis of BODIPY-based supramolecular PSs with quaternary-ammonium moieties for mitochondrial targeting.
- Evaluation of PSs' ability to generate reactive oxygen species (ROS) and induce pyroptosis upon light irradiation.
- Utilizing transmission electron microscopy, Calcein AM/Co2+ imaging, immunofluorescence, and Western blot to analyze mitochondrial damage and signaling pathways.
Main Results:
- The designed PSs effectively accumulate in mitochondria and generate ROS upon irradiation, leading to significant pyroptosis.
- Mitochondrial membrane damage and cardiolipin (CL) externalization were observed, indicating critical events in pyroptosis induction.
- A positive feedback loop involving the caspase-3/GSDME pathway and amplified mitochondrial content release was identified, sustaining pyroptotic cell death.
- The PSs demonstrated significant antitumor efficacy in preclinical mouse models.
Conclusions:
- Mitochondria-targeted supramolecular PSs can effectively induce pyroptosis via simultaneous caspase-3/GSDME activation and CL externalization.
- These PSs offer a promising strategy for developing advanced PDT-based cancer therapies.
- The identified mechanism provides insights into enhancing pyroptosis induction for improved therapeutic outcomes.
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