Programming cell pyroptosis with biomimetic nanoparticles for solid tumor immunotherapy

Abstract

Immunotherapy shows remarkable efficacy in treating several types of cancer such as melanoma, leukemia, and lung carcinoma, but its therapeutic effect for most solid tumors is still limited. Various cancer therapies, such as chemotherapy, radiotherapy and phototherapy, kill solid tumors through non-inflammatory apoptosis or ablation, rather than making solid tumors immunogenic. As a highly-inflammatory programmed cell death (PCD), pyroptosis provides a great opportunity to alleviate immunosuppression and promote a systemic immune response in treating solid tumors. Herein, by fusing breast cancer membrane onto the poly(lactic-co-glycolic acid) polymeric core, we design a biomimetic nanoparticle (BNP) loaded with indocyanine green (ICG) and decitabine (DCT) for photo-activated cancer cell pyroptosis and solid tumor immunotherapy. The tumor-homing BNP effectively accumulate in tumor with low immunogenicity. ICG in BNP puncture cancer cell membranes induces a sharp cytoplasm Ca2+ concentration increase by low-dose NIR photo-activation, which promotes cytochrome c release followed by caspase-3 activation. DCT up-regulates GSDME expression synergistically via inhibiting DNA methylation, which enhances caspase-3 cleavage to GSDME and causes cancer cell pyroptosis. Finally, photo-activated pyroptosis mediated by BNP induces an impressive systemic antitumor immunity for inhibition of both primary tumor and distant tumors. Overall, pyroptosis-associated BNP shows a novel strategy for solid tumor immunotherapy with high compatibility and wide clinical applicability.