A HO-1 gene knockout using a NanoCRISPR scaffold suppresses metastasis in mouse models

Photodynamic therapy-induced immunogenic cell death has the potential to generate autologous cancer vaccines. However, the innate or evolved genetic tolerance of tumours limits the efficacy of this approach. Here we report the development of a heritable nanoplatform based on gene editing of haem oxygenase-1 (HO-1) using a NanoCRISPR/HO-1 scaffold. This platform effectively eliminates genetic tolerance to reactive oxygen species in tumours without causing adverse effects on main immune cells, resulting in a robust and durable immune response to autologous vaccine. This NanoCRISPR scaffold can inherit susceptibility to tumour progeny, transforming heterogeneous malignancies into a reactive oxyen species-sensitive phenotype. Moreover, the arginine-grafted polyethyleneimine module and CpG motif within the NanoCRISPR scaffold enhance the cancer-immune cycle by amplifying antigen generation, promoting T cell proliferation and activating adaptive immune response in cancer models. When combined with an αPD-L1 antibody, the NanoCRISPR scaffold-based heritable nanoplatform elicits antitumour immunity and durable immunological memory in vivo melanoma mouse models. This combinational therapy evokes a strong immune memory against tumour rechallenge, providing insights into the rational development of a cancer vaccine regimen.