Beyond Static Architectures: Responsive Tetrahedral Framework Nucleic Acids for Precise Theranostics

Abstract Precise theranostics requires spatiotemporal control and high specificity to adapt to complex physiological microenvironments. Tetrahedral framework nucleic acids (tFNA), classic 3D DNA nanostructures, offer distinct advantages such as atomic-level structural precision, intrinsic programmability, and excellent biocompatibility. While traditional static tFNA lack dynamic responsiveness to external stimuli─severely limiting their clinical translation potential─the emergence of dynamically responsive tFNA has garnered increasing attention. These smart systems offer substantial advantages, including stimulus-triggered structural reconfiguration, targeted payload release, and real-time signal transduction. Despite rapid design innovations, a systematic summary of dynamic tFNA strategies remains lacking. Accordingly, we synthesize the design principles of responsive tFNA by categorizing their mechanisms into conformational rearrangement, chemical bond cleavage, and toehold-mediated strand displacement logic. We highlight their applications in precision diagnosis, smart therapeutics, and theranostics integration and discuss critical challenges in biological stability, scalable manufacturing, and biosecurity. By mapping current advancements and unresolved hurdles, this work provides a comprehensive reference for the rational design of responsive DNA nanodevices and discusses the challenges associated with the clinical translation of dynamic tFNA.