DNA Nanotechnology-Based Robotic Devices for Frontier Applications in Healthcare.

Over the past decade, DNA nanotechnology has enabled the design of diverse programmable nanostructures, accelerating the emergence of DNA nanotechnology-based robotic devices (DNRDs) for advanced healthcare applications. Recent developments in DNA origami, DNA walkers, and molecular logic circuits have enabled dynamic and stimuli-responsive systems capable of functioning as logic-gated nanopills, precision biosensors, and autonomous therapeutic agents. These programmable devices also support cargo sorting, molecular actuation, and externally controlled operations triggered by optical, thermal, pH, enzymatic, or electromagnetic stimuli. Despite these advances, several challenges continue to limit clinical translation, including maintaining structural stability in complex physiological environments, achieving scalable and cost-effective manufacturing, and addressing regulatory and safety considerations, particularly those associated with immunogenicity, toxicity, off-target activity, unintended activation, biodistribution, and long-term biological fate. In this review, we comprehensively discuss the evolution, design principles, and mechanistic foundations of DNRDs, highlight recent technological advances, and critically evaluate their expanding roles in diagnostics, therapeutics, and synthetic biology. We further discuss current translational limitations and emerging strategies required to improve their safety, robustness, scalability, and clinical applicability. Finally, future directions toward the development of increasingly programmable, responsive, and clinically translatable DNRDs are presented.