Self‐Driven CuAAC Reaction Catalyzed by Photosensitive Biohybrids Energized by Lactate for Boosting Cancer Immunotherapy

Abstract As a typical bioorthogonal reaction, the copper (I) catalyzed azide‐alkyne 1,3‐cycloaddition (CuAAC) reaction strongly depends on the reducing agents and the rate of the CuAAC reaction is far from sufficient to produce drug agents under physiological conditions. It is necessary and highly demanding to develop an efficient CuAAC reaction without using chemical reducing agents. Herein, inspired by the extracellular electron transfer (EET) mechanisms of the electroactive bacteria within the realm of synthetic biology, a photo‐assisted targeting electroactive bacteria equipped bioorthogonal catalyst system for boosting cancer immunotherapy is constructed. The bacteria specifically anaerobically catabolize lactate at the tumor site, accompanied by transferring electrons to the bioorthogonal catalyst, thereby triggering the CuAAC reaction to produce active drugs in situ. Strikingly, under illumination, the photoelectrons generated by attached AuNPs can be transported into bacterial cytoplasm to accelerate the CuAAC reaction by promoting cellular metabolism. The biohybrid enables synergistic immunogenic cell death (ICD), immune checkpoint blockade (ICB) immunotherapy and alleviation of immunosuppressive microenvironment. Ingeniously, ICD and lactate consumption both boost the efficacy of ICB immunotherapy. Overall, the system provides a bridge between the tumor metabolism and CuAAC reaction through bacterial respiration, offering fascinating opportunities for controlled synthesis of active molecules by bioorthogonal catalysis.