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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
PubMed

Insights

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.
Keywords:
photodynamic therapyphotosensitizerpyroptosisreactive oxygen speciesself‐assembly

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