A Bioinspired Cell Membrane Disruptor Opens Pyroptosis-deficient Cells Membrane and Ignites Powerful Antitumour Immune Function

Gasdermin protein, a membrane disruptor, can mediate immunogenic pyroptosis and elicit anti-tumour immune function. However, cancer cells downregulate gasdermin and develop membrane repair mechanisms to resist pyroptosis. Therefore, an artificial membrane disruptor (AMD) that can directly mediate membrane rupture in pyroptosis-deficient cells and induce antitumour immune responses in a controllable manner is valuable in preclinical and clinical research. Here, we have established a micron-scale Ce6-based artificial membrane disruptor (AMD) to directly induce plasma membrane rupture (PMR) in gasdermin-deficient tumour cells. Compared to free Ce6 molecules, micron-scale AMDs specifically localised Ce6 to the plasma membrane without labelling other organelles. Due to the plasma membrane specificity, AMDs mediated irreversible and fast PMR under 660 nm red light. In addition, our AMDs were able to mediate PMR and lytic cell death in a catalytic manner, such that the Ce6 used by AMDs is one-fifth that of Ce6 alone when mediating 80% of cancer cell death. In vivo, our AMDs exhibited tumour targeting and penetration, indicating that light-driven PMR was tumour specific. We applied AMDs to antitumour therapy in gasdermin-deficient tumours, the results showed that all tumours could be efficiently eliminated with negligible damage to major organs by synergising with anti-PD-1 therapy. Tumour regression was correlated with PMR-mediated inflammation and T-cell-based immune responses. Our study provides new insights for designing the bioinspired membrane disruptor for PMR and mediating anti-tumour immunotherapy. In addition, AMD is a reliable tool for investigating the immunogenicity of PMR in vitro and in vivo.