Unveiling the Potential of Tetrahedral DNA Frameworks in Clinical Medicine: Mechanisms, Advances, and Future Perspectives

As deoxyribonucleic acis (DNA) nanotechnology advances, DNA, a fundamental biological macromolecule, has been employed to treat various clinical diseases. Among the advancements in this field, tetrahedral frameworks nucleic acids (tFNAs) have gained significant attention due to their straightforward design, structural simplicity, low cost, and high yield since their introduction by Turberfield in the early 2000s. Due to its stable spatial structure, tFNAs can resist the impact of innate immune responses on DNA and nuclease activity. Meanwhile, structural programmability of tFNAs allows for the development of static tFNA-based nanomaterials through the engineering of functional oligonucleotides or therapeutic molecules and dynamic tFNAs through the attachment of stimuli-responsive DNA apparatuses. This review first summarizes the key merits of tFNAs, including natural biocompatibility, biodegradability, structural stability, unparalleled programmability, functional diversity, and efficient cellular internalization. Based on these strengths, this review comprehensively analyzes applications of tFNAs in different clinical settings, including orthopedics, stomatology, urinary system diseases, liver-related diseases, tumors, infection, neural system diseases, ophthalmic diseases, and immunoprophylaxis. We also discuss the limitations of tFNAs and the challenges encountered in preclinical studies. This review provides new perspectives for future research and valuable guidance for researchers working in this field.