Bioorthogonal Activation of Deep Red Photoredox Catalysis Inducing Pyroptosis

Area of Science:

• Bioorganic Chemistry
• Photocatalysis
• Biotechnology

Background:

• Photoredox catalysis offers powerful tools for chemical synthesis and biological applications.
• Integrating artificial photoredox catalysts into living systems faces challenges like poor targeting, biocompatibility, and toxicity.
• Developing controllable and safe photocatalytic systems for intracellular applications is crucial.

Purpose of the Study:

• To develop a novel bioorthogonally activatable photoredox catalysis system for spatiotemporal control within living cells.
• To address limitations of existing photoredox catalysts, including targetability, biocompatibility, and toxicity.
• To demonstrate the potential of this approach for manipulating cellular processes and inducing cancer cell death.

Main Methods:

• Designed and synthesized a bioorthogonally activatable photocatalyst (PC-Tz) by modifying a rhodamine core.
• Quenched photocatalytic activity using 1,2,4,5-tetrazine, which was restored via an intracellular inverse electron-demand Diels-Alder (iEDDA) reaction with trans-cyclooctene (TCO).
• Localized the TCO in mitochondria to achieve targeted activation of the photocatalyst within cancer cells.

Main Results:

• Demonstrated successful restoration of photocatalytic activity specifically in mitochondria via the iEDDA reaction.
• Showcased photocatalytic oxidation of nicotinamide adenine dinucleotide (NADH), leading to manipulation of the mitochondrial electron transport chain (ETC) under hypoxia.
• Observed induction of pyroptotic cell death through the caspase-3/gasdermin E (GSDME) pathway, resulting in antitumor efficacy and reduced ATP levels in cancer cells.

Conclusions:

• This study presents the first example of bioorthogonally activatable photoredox catalysis.
• The developed system enables precise spatiotemporal control of photocatalytic activity in specific organelles without disrupting native biological processes.
• This innovative approach opens new possibilities for developing targeted therapies and diagnostic tools in biotechnology.