Botulinum Proteases Reprogrammed to Target Cancer Cells

This study explores a novel approach to cancer treatment by reprogramming botulinum neurotoxin serotype X proteases. Researchers used phage-assisted evolution to modify these proteases to cleave and activate procaspase-1 and gasdermin D, which are key effectors of inflammatory cell death. The evolved proteases demonstrated the ability to trigger robust cell death across multiple cancer cell lines. Notably, the gasdermin D-cleaving protease induced lytic death, while the procaspase-1-cleaving variant initiated both lytic and apoptotic cell death. To enhance delivery, the proteases were combined with a native BoNT translocation domain, allowing selective targeting of cancer cells while sparing healthy ones. In a drug-resistant tumor mouse model, the expression of the evolved protease targeting caspase-1 significantly reduced tumor growth. These findings suggest that botulinum proteases could be developed as programmable tools for targeted cancer therapy, offering a new avenue for treatment. However, the summary is based solely on the abstract, and further details from the full paper are needed to fully understand the scope and limitations of the study.