A pyroptosis nanotuner for cancer therapy

On 23 May 2022, Yiguang Wang, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, China, and Fuping You, Institute of Systems Biomedicine, Department of Immunology, Beijing Key Laboratory of Tumour Systems Biology, Peking University Health Science Center, China, and their team published a paper titled “A pyroptosis nanotuner for cancer therapy” in Nature Nanotechnology, which offers new insights into how to engineer nanomedicines with tunable pyroptosis activity through specific targeting of distinct endocytic signalling for biomedical applications.

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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.