Communicative Nanomotors Reprogram Cancer Cell Death via Pyroptosis

Nanomotors offer significant advantages over passive nanoparticles in biomedical applications. However, their potential has been largely restricted to cargo transport, with limited capacity for interaction with biological systems. Here, we present next‐generation self‐assembled nanomotors that not only exhibit chemotactic motility but also actively communicate with cells, reprogramming cell fate by inducing pyroptosis. These nanomotors are designed to respond to elevated reactive oxygen species (ROS) in the tumor microenvironment, triggering nitric oxide (NO)‐driven propulsion and selective mitochondria targeting via triphenylphosphine (TPP) surface engineering. This interaction induces mitochondrial damage, cytochrome c release, and activation of gasdermin E (GSDME)‐mediated pyroptosis. Furthermore, their chemotactic motility facilitates deeper tumor tissue penetration in 3D spheroids, demonstrating their ability to navigate physiological barriers. By shifting the paradigm from motility‐driven to interactive nanomedicine, this study establishes a transformative platform for targeted cancer therapy.