A general strategy towards early endosome-stressed nanophotosensitizers for pyroptotic cancer therapy

Emerging evidence has revealed that induction of pyroptosis is a promising strategy for cancer therapy. However, it remains challenging to specifically evoke pyroptotic cancer cell death paradigm while sparing other programmed cell death pathways. Here, we report a general nanostrategy towards elicitation of precise oxidative stress in early endosomes (EE) by several nanosized photosensitizers (NPS) for robust pyroptotic cancer therapy. The spatiotemporally subcellular trafficking of NPS can regularly tune the pyroptosis-inducing activity of endocytic organelle stress. NPS-enabled EE oxidative stress (NPS_ee) initiates universal and robust gasdermin-E-mediated pyroptosis across different nanocarriers and cancer cell lines with up to 21.4-fold higher sensitivity, as compared with the traditional lysosomal stress. This EE-stressed nanostrategy achieves complete eradication of primary tumors with efficient immune response and long-lasting cancer prevention. This study provides guidelines for design of nanomedicines with pyroptosis-inducing activity for cancer therapy.