Research Advances on Tetrahedral Framework Nucleic Acids in Diseases of the Skeletal, Joint, Spinal, Nervous, and Muscular Systems

Objectives Tetrahedral framework nucleic acids (tFNAs) are DNA nanomaterials characterized by a three-dimensional tetrahedral structure. Owing to their excellent programmability, structural stability, biocompatibility and efficient cellular uptake, tFNAs have emerged as promising platforms in the biomedical field. This review aims to systematically summarise the core biological advantages of tFNAs and their latest research progress in the treatment of multi-system diseases, thereby providing a reference for further investigation and clinical translation. Methods We comprehensively reviewed recent literature on tFNAs, focusing on their intrinsic biological activities and their applications either as standalone therapeutic agents or as drug delivery carriers. Particular attention was paid to studies involving the skeletal, joint, spinal, nervous and muscular systems. Results tFNAs exert direct regulatory effects on cell proliferation, migration and differentiation, and possess intrinsic capabilities for scavenging reactive oxygen species and suppressing inflammatory responses. As therapeutic agents or nanocarriers, tFNAs have shown promising efficacy in a range of conditions, including avascular necrosis of the femoral head, bone defects, osteoarthritis, intervertebral disc degeneration, nerve injury and sarcopenia. The functionalisation of tFNAs with aptamers, drugs or signaling molecules further enhances their targeting specificity and therapeutic potency. Conclusions The unique structural and biological properties of tFNAs position them as versatile tools for treating diseases across multiple systems. Future efforts should focus on optimising drug-loading strategies, elucidating long-term biosafety profiles, and advancing well-designed preclinical and clinical studies to accelerate the translational application of tFNAs.