Potential Applications of the Tetrahedral Framework Nucleic Acid in Orthopaedics.

Tetrahedral framework nucleic acids (tFNA) are specialised three-dimensional DNA nanostructures with precise self-assembly, structural rigidity, programmability, and excellent biocompatibility. Their resistance to enzymatic degradation is enabled by their unique tetrahedral geometry, which also facilitates efficient cellular internalisation without the need for transfection agents. Thus, establishing tFNA as both a versatile regulator and a nanocarrier. Healing in orthopaedics is often stalled by limited tissue regeneration, unpredictable inflammation and infection, and suboptimal drug localisation within complex microenvironments. This review summarises recent advances in the application of tFNA across key orthopaedic domains, including bone and cartilage regeneration, angiogenesis, immunomodulation, anti-microbial therapy, and bone cancer treatment. tFNA have been shown to enhance osteogenic and chondrogenic differentiation of multiple mesenchymal stem cell populations by indirectly activating the Wnt/β-catenin and PI3K/AKT pathways. When functionalised with peptides, small molecules, nucleic acids, or natural compounds, tFNA promote angiogenesis, suppress oxidative stress, inhibit inflammatory and pyroptotic signalling, and restore extracellular matrix homeostasis in degenerative joint diseases. Furthermore, integration of tFNA with antibiotics, antimicrobial peptides, hydrogels, and implant surfaces demonstrates promising efficacy in combating orthopaedic infections and biofilm formation while supporting tissue regeneration. Emerging tFNA-based delivery systems for osteosarcoma therapy further illustrate their translational versatility. Despite these encouraging findings, several challenges hinder clinical translation: large-scale synthesis, long-term biosafety, immune responses, pharmacokinetics, and controlled degradation within mechanically and biologically complex orthopaedic environments. Interdisciplinary research and optimisation are ongoing to advance tFNA-based platforms toward safe, effective, and personalised nanotherapeutic strategies in orthopaedics. These developments may ultimately redefine precision therapies for the global management of musculoskeletal diseases.