With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids (tFNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, tFNAs have been widely applied in the biomedical field as three-dimensional DNA nanomaterials. Surprisingly, tFNAs exhibit positive effects on cellular biological behaviors and tissue regeneration, which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity, tFNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization, intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic tFNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic tFNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone, cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.

The physicochemical nature of DNA allows the assembly of highly predictable structures via several fabrication strategies, which have been applied to make breakthroughs in various fields. Moreover, DNA nanostructures are regarded as materials with excellent editability and biocompatibility for biomedical applications. The ongoing maintenance and release of new DNA structure design tools ease the work and make large and arbitrary DNA structures feasible for different applications. However, the nature of DNA nanostructures endows them with several stimulus-responsive mechanisms capable of responding to biomolecules, such as nucleic acids and proteins, as well as biophysical environmental parameters, such as temperature and pH. Via these mechanisms, stimulus-responsive dynamic DNA nanostructures have been applied in several biomedical settings, including basic research, active drug delivery, biosensor development, and tissue engineering. These applications have shown the versatility of dynamic DNA nanostructures, with unignorable merits that exceed those of their traditional counterparts, such as polymers and metal particles. However, there are stability, yield, exogenous DNA, and ethical considerations regarding their clinical translation. In this review, we first introduce the recent efforts and discoveries in DNA nanotechnology, highlighting the uses of dynamic DNA nanostructures in biomedical applications. Then, several dynamic DNA nanostructures are presented, and their typical biomedical applications, including their use as DNA aptamers, ion concentration/pH-sensitive DNA molecules, DNA nanostructures capable of strand displacement reactions, and protein-based dynamic DNA nanostructures, are discussed. Finally, the challenges regarding the biomedical applications of dynamic DNA nanostructures are discussed.

The significant clinical feature of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is the exposure of the necrotic jaw. Other clinical manifestations include jaw pain, swelling, abscess, and skin fistula, which seriously affect the patients’ life, and there is no radical cure. Thus, new methods need to be found to prevent the occurrence of BRONJ. Here, a novel nanoparticle, tFNA-KLT, was successfully synthesized by us, in which the nanoparticle tetrahedral framework nucleic acid (tFNA) was used for carrying angiogenic peptide, KLT, and then further enhanced angiogenesis. TFNA-KLT possessed the same characteristics as tFNA, such as simple synthesis, stable structure, and good biocompatibility. Meanwhile, tFNA enhanced the stability of KLT and carried more KLT to interact with endothelial cells. First, it was confirmed that tFNA-KLT had the superior angiogenic ability to tFNA and KLT both in vitro and in vivo. Then we apply tFNA-KLT to the prevention of BRONJ. The results showed that tFNA-KLT can effectively prevent the occurrence of BRONJ by accelerating angiogenesis. In summary, the prepared novel nanoparticle, tFNA-KLT, was firstly synthesized by us. It was also firstly confirmed by us that tFNA-KLT significantly enhanced angiogenesis and can effectively prevent the occurrence of BRONJ by accelerating angiogenesis, thus providing a new avenue for the prevention of BRONJ and a new choice for therapeutic angiogenesis.