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Evolution of botulinum neurotoxin serotype X proteases to induce inflammatory cell death in cancer cells
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DOI：10.1038/s41587-026-03243-9.png)
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Abstract
En 中文
Triggering protease-activated cell death is a promising strategy for cancer treatment. Here, we used phage-assisted evolution to reprogram botulinum neurotoxin serotype X proteases to cleave and activate procaspase-1 and gasdermin D, key effectors of inflammatory cell death. We also developed an efficient system to broadly characterize the substrate specificity of wild-type and evolved botulinum neurotoxin serotype X protease variants. Evolved proteases triggered robust cell death across multiple cancer cell lines. The gasdermin D-cleaving protease exclusively induced lytic death, whereas the procaspase-1-cleaving variant initiated both lytic and apoptotic cell death. To enable self-delivery into mammalian cells, we reconstitute evolved proteases with a native BoNT translocation domain, selectively killing cultured cancer cells while sparing non-cancerous cells. Expression of the evolved protease targeting caspase-1 reduced tumor growth in a highly drug-resistant tumor mouse model. These findings establish an evolving protease system to modulate inflammatory cell death and highlight the potential of BoNT proteases as programmable tools for targeted cancer therapy. Directed evolution of proteases induces targeted, multipathway lytic cell death in cancer cells.
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41.7
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1.2W
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10.1W
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Cited Papers