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

Abstract

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.

Nanohybrid-Based Redox Homeostasis Perturbators Escaped from Early Lysosomes toward Amplified Sensitization of Tumor Cells and Photothermally Maneuvered Pyroptosis Therapy

“…Inhibition of autophagy can effectively promote cellular metastability, thereby enhancing the efficiency of pyroptosis. 43 In addition, the combination of LMP and autophagy inhibition may further contribute to lysosomal stress.…”

Galvanic replacement synthesis of PtPdAu hollow nanorods as peroxidase mimic with high specific activity for colorimetric detection

“…Noble metal materials, especially platinum (Pt) or palladium (Pd), exhibit ultra-high activities in many catalytic applications. 14,15 So far, many noble metal nanomaterials have been shown to possess intrinsic enzyme-like properties. 16,17 For example, PtPd bimetallic porous nanorods prepared by a hydrothermal method revealed high peroxidase-like catalytic performance and were applied in the colorimetric detection of H 2 O 2 , 18 and PtPdAu alloys obtained by introducing Au nanoparticles onto PtPd micelles successfully served as dual-mode nanoplatforms for colorimetric sensing in hierarchical diabetic detection.…”

An Alkaline Nanocage Continuously Activates Inflammasomes by Disrupting Multiorganelle Homeostasis for Efficient Pyroptosis

“…The normal physiological activities of cells are positively correlated with homeostasis and cooperation between organelles. Conversely, cell death, such as apoptosis and pyroptosis, is usually related to the destruction of the organelle homeostasis of organelles. − However, the induction of pyroptosis by disrupting single-organelle homeostasis is greatly restricted by the cytoprotective mechanisms, which are based on the cooperation between organelles. , In comparison to normal cells, cancer cells are more sensitive to imbalances in lysosomal homeostasis. , Of note, lysosome-associated autophagy plays a vital role in regulating organelle homeostasis, which is involved in ER, centrosomes, and endosomes. − Under normal conditions, ER–endosome membrane contact sites (EECS) inhibit the recruitment and subsequent transfer of the NLRP3 inflammasome to the centrosome by the endosome. , Disturbing EECS by inducing ER stress can enhance NLRP3 inflammasome activation, increasing the potential to induce pyroptosis. ,, However, lysosome-associated autophagy can alleviate ER stress by degrading the stressed ER. − In addition, the fusion of autophagosomes with lysosomes can promote the degradation of overexpressed inflammasomes. , Consequently, these cytoprotective mechanisms reduce the potential for pyroptosis mediated by disrupting single-organelle homeostasis. Therefore, it is extremely desirable to establish a new strategy to disrupt the self-protection of cells for highly efficient pyroptosis.…”