Oral TRAP1-Targeting CRISPR Therapy Boosts Colorectal Cancer Treatment in Multiple Disease Models

Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for approximately 10% of all cancer cases and is the second leading cause of cancer-related deaths globally (source: WHO).

While screening programmes and increased awareness about lifestyle-related risk factors have contributed to an overall drop in the rate of older people being diagnosed with CRC since the mid-1980s, the incidence of CRC actually increased by 2.4 % in people below the age of 50 years from 2012 to 2021 (source: American Cancer Society).

In those who develop CRC, diagnosis often occurs when the disease is advanced, with systemic chemotherapy – sometimes in combination with targeted therapies depending on patient-specific mutations – being the primary treatment approach.

Unfortunately, chemoresistance and immunosuppression hamper the efficacy of chemoimmunotherapy in CRC, and both events are in part regulated by mitochondrial chaperone proteins.

One gene that is overexpressed in a large number of CRC cases and has been linked with poor prognosis and chemotherapy resistance is TRAP1; this gene encodes the tumour necrosis factor receptor-associated protein 1, which functions as a mitochondrial molecular chaperone.

In an article published this week in Nature Nanotechnology, researchers in China report that TRAP1 disruption results in the continuous opening of the mitochondrial permeability transition pore in CRC cells, leading to enhanced chemotherapy-induced cell necrosis and promotion of anti-tumour immune responses.

Following those findings, the team designed an oral CRISPR-Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes to disrupt TRAP1 in CRC. They found that this system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. The team reports that chemotherapeutic efficacy is augmented by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with synergistic anti-tumour effects. The findings highlight a potentially new avenue for the treatment of advanced CRC.

Read the full article entitled 'An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer' here.