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

Chemoresistance and immunosuppression are common obstacles that hinder the efficacy of chemo-immunotherapy in colorectal cancer (CRC), which are closely related to mitochondrial chaperone proteins. Here we show that the disruption of the TRAP1 gene, which encodes a mitochondrial chaperone in tumor cells, can cause the translocation of cyclophilin D (CypD). This translocation results in the continuous opening of the mitochondrial permeability transition pore (mPTP), which enhances chemotherapy-induced cell necrosis and promotes immune responses. Based on this discovery, an oral CRISPR/Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes was developed to disrupt the TRAP1 gene in CRC. The oral CRISPR/Cas9 delivery system was found to accumulate in CRC tissues by penetrating the intestinal mucus layer and undergoing epithelial transcytosis. It could effectively enhance chemotherapeutic efficacy by overcoming the chemoresistance and induced the following immunoactivated tumor microenvironment (TME) in both orthotopic and chemoresistant CRC models, demonstrating remarkable synergetic antitumor effects. This oral CRISPR/Cas9 delivery system represents a promising therapeutic strategy by overcoming barriers of chemoresistance and immunosuppression in CRC for promoting the clinical management.