Engineered caspases directly rewire mutant Ras to cell death

As central executioners of cell death, caspases that activate exclusively in diseased cells would provide powerful and specific therapeutic agents. Natural caspase regulation exhibits two universal features that facilitate the engineering of such caspases: proximity-induced subunit assembly and modular separation of substrate recruitment from catalysis. Here, we take advantage of these features to engineer “Raspases,” split effector caspases that conditionally reconstitute active complexes upon detection of mutant Ras, an oncogene altered in roughly a quarter of all cancers. When delivered as mRNA in lipid nanoparticles, Raspases selectively eliminate Ras-mutant human cancer lines while sparing wild-type cells. The system is built entirely from human protein domains, can be encoded as a single polyprotein, and can be adapted to trigger pyroptosis. Critically, Raspases match or exceed the potency of alternative Ras-targeting interventions in vitro. These results establish retargeted caspases as a generalizable sense-and-kill platform for selective elimination of diseased cells.