Bioorthogonal Disruption of Pyroptosis Checkpoint for High-Efficiency Pyroptosis Cancer Therapy

Pyroptosis is an inflammatory form of programmed cell death that holds great promise in cancer therapy. However, autophagy as the crucial pyroptosis checkpoint and the self-protective mechanism of cancer cells significantly weakens the therapeutic efficiency. Here, a bioorthogonal pyroptosis nanoregulator is constructed to induce pyroptosis and disrupt the checkpoint, enabling high-efficiency pyroptosis cancer therapy. The nanoregulator allows the in situ synthesis and accumulation of the photosensitizer PpIX in the mitochondria of cancer cells to directly produce mitochondrial ROS, thus triggering pyroptosis. Meanwhile, the in situ generated autophagy inhibitor via palladium-catalyzed bioorthogonal chemistry can disrupt the pyroptosis checkpoint to boost the pyroptosis efficacy. With the biomimetic cancer cell membrane coating, this platform for modulating pyroptosis presents specificity to cancer cells and poses no harm to normal tissue, resulting in a highly efficient and safe antitumor treatment. To our knowledge, this is the first report on a disrupting intrinsic protective mechanism of cancer cells for tumor pyroptosis therapy. This work highlights that autophagy as a checkpoint plays a key regulative role in pyroptosis therapy, which would motivate the future design of therapeutic regimens.