Pyroptosis-based nanomedicine shows great potential to unchoke the bottlenecks of cancer immunotherapy, but hindered by precise and specific regulation of pyroptosis in tumor cells. Herein, we report an endogenous/exogenous stimulus-activatable unimolecular polyprodrug as nano-inducer (denoted as CCNP) to precisely regulate the process of gasdermin E (GSDME)-medicated tumor pyroptosis. This nano-inducer is specifically switched by noninvasive laser radiation and tumor microenvironment reactive oxygen species (ROS) and glutathione (GSH), and activates caspase-3, thus triggering GSDME-mediated pyroptosis. This three-pronged induced model of pyroptosis can fully play the therapeutic potency of combined chemotherapy and photodynamic therapy exported by nano-inducer, suggests a new perspective on how to multi-stimulus-responsive nanomedicine induces and precisely regulates the tumor cell pyroptosis for assisting immune checkpoint blockade therapy.

基于细胞焦亡的纳米药物显示出消除癌症免疫治疗瓶颈的巨大潜力，但受到肿瘤细胞细胞焦亡精确和特异性调节的阻碍。在此，我们报道了一种内源性/外源性刺激可激活的单分子多聚前药作为纳米诱导剂（表示为 CCNP），以精确调节 gasdermin E (GSDME) 药物治疗的肿瘤细胞焦亡过程。这种纳米诱导剂通过非侵入性激光辐射和肿瘤微环境活性氧 (ROS) 和谷胱甘肽 (GSH) 进行特异性切换，并激活 caspase-3，从而引发 GSDME 介导的细胞焦亡。这种三管齐下的细胞焦亡模型可以充分发挥纳米诱导剂输出的联合化疗和光动力治疗的治疗效能，