Bioorthogonal dissociative rhenium(i) photosensitisers for controlled immunogenic cell death induction

Photosensitisers for photoimmunotherapy with high spatiotemporal controllability are rare. In this work, we designed rhenium(i) polypyridine complexes modified with a tetrazine unit via a bioorthogonally activatable carbamate linker as bioorthogonally dissociative photosensitisers for the controlled induction of immunogenic cell death (ICD). The complexes displayed increased emission intensities and singlet oxygen ((1)O(2)) generation efficiencies upon reaction with trans-cyclooct-4-enol (TCO-OH) due to the separation of the quenching tetrazine unit from the rhenium(i) polypyridine core. One of the complexes containing a poly(ethylene glycol) (PEG) group exhibited negligible dark cytotoxicity but showed greatly enhanced (photo)cytotoxic activity towards TCO-OH-pretreated cells upon light irradiation. The reason is that TCO-OH allowed the synergistic release of the more cytotoxic rhenium(i) aminomethylpyridine complex and increased (1)O(2) generation. Importantly, the treatment induced a cascade of events, including lysosomal dysfunction, autophagy suppression and ICD. To the best of our knowledge, this is the very first example of using bioorthogonal dissociation reactions as a trigger to realise photoinduced ICD, opening up new avenues for the development of innovative photoimmunotherapeutic agents.