An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer

Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 (TRAP1) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses. On the basis of this discovery we developed an oral CRISPR-Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes that disrupts the TRAP1 gene in CRC. This system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. It enhances chemotherapeutic efficacy by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with remarkable synergistic antitumour effects. This oral CRISPR-Cas9 delivery system represents a promising therapeutic strategy for the clinical management of CRC.