Pyroptosis is a gasdermin-mediated programmed necrosis that occurs via membrane perforation and that can be exploited for biomedical applications in cancer therapy. However, inducing specific pyroptotic cancer cell death while sparing normal cells is challenging. Here, we report an acid-activatable nanophotosensitizer library that can be used to spatiotemporally target distinct stages of endosomal maturation, enabling tunable cellular pyroptosis. Specific activation of phospholipase C signalling transduction in early endosomes triggers gasdermin-E-mediated pyroptosis, which is dramatically reduced when acid-activatable nanophotosensitizers are transported into late endosomes/lysosomes. This nanotuner platform induces pyroptotic cell death with up to 40-fold tunability in various gasdermin-E-positive human cancers, resulting in enhanced anti-tumour efficacy and minimized systemic side effects. This study offers new insights into how to engineer nanomedicines with tunable pyroptosis activity through specific targeting of distinct endocytic signalling for biomedical applications.

Pyroptosis 是一种gasdermin 介导的程序性坏死，通过膜穿孔发生，可用于癌症治疗中的生物医学应用。然而，在保留正常细胞的同时诱导特定的细胞焦亡癌细胞死亡具有挑战性。在这里，我们报告了一种可酸激活的纳米光敏剂库，可用于时空靶向内体成熟的不同阶段，从而实现可调节的细胞焦亡。早期内体中磷脂酶 C 信号转导的特异性激活会触发 gasdermin-E 介导的细胞焦亡，当酸激活的纳米光敏剂被转运到晚期内体/溶酶体中时，焦亡会显着降低。这种纳米调谐器平台在各种 gasdermin-E 阳性人类癌症中诱导细胞焦亡，可调谐性高达 40 倍，从而增强抗肿瘤功效并最大限度地减少全身副作用。这项研究为如何通过针对生物医学应用的不同内吞信号的特异性靶向来设计具有可调焦亡活性的纳米药物提供了新的见解。