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Acute kidney injury (AKI) is not only a worldwide problem with a cruel hospital mortality rate but also an independent risk factor for chronic kidney disease and a promoting factor for its progression. Despite supportive therapeutic measures, there is no effective treatment for AKI. This study employs tetrahedral framework nucleic acid (tFNA) as a vehicle and combines typhaneoside (Typ) to develop the tFNA-Typ complex (TTC) for treating AKI. With the precise targeting ability on mitochondria and renal tubule, increased antiapoptotic and antioxidative effect, and promoted mitochondria and kidney function restoration, the TTC represents a promising nanomedicine for AKI treatment. Overall, this study has developed a dual-targeted nanoparticle with enhanced therapeutic effects on AKI and could have critical clinical applications in the future.

The past decades have witnessed the development of DNA nanotechnology and the emergence of various spatial DNA nanostructures, from two-dimensions to three-dimensions. The typical example is the tetrahedral framework nucleic acid (tFNA). In this review, we summarize the progress in fabrication, modification of tFNA-based functional systems and their potentials in biomedical applications. Through a one-step assembly process, tFNA is synthesized via four single stranded DNAs with three short sequences complementary to the other sequence of another single strand. Characterizations including polyacrylamide gel electrophoresis, atomic force microscopy, and dynamic light scattering measurement show tFNA as a pyramid-like nanostructure with the size of around 10 nm. Feathered with intrinsic biocompatibility and satisfactory cellular membrane permeability, the first generation of tFNA shows promising capacities in regulating cell biological behavior, promoting tissue regeneration, and immunomodulation. Along with excellent editability and relative biostability in complicated conditions, tFNA could be modified via hanging functional domains on the vertex or side arm and incorporating small-molecular-weight drugs to form the second generation, for reversing multidrug resistance in tumor cells or microorganisms, target therapy, anticancer and antibacterial treatments. The third generation of tFNA is currently tried via a multistep assembly process for stimuli-response and precise drug release. Although tFNAs show promising potentials in cargo delivery, massive efforts still need to be made to improve biostability, maximal load, and structural controllability.

Bisphosphonates are often used to treat osteoporosis, malignant bone metastases, and hypercalcemia. However, it can cause serious adverse reactions, bisphosphonate-related osteonecrosis of the jaw (BRONJ), which seriously affects the quality of life of patients. At present, the treatment of BRONJ is still difficult to reach an agreement, and there is no effective treatment. Therefore, it is very important to find effective treatments. Many studies have shown that the occurrence of BRONJ may be due to unbalanced bone turnover, anti-angiogenesis, bacterial infection, direct tissue toxicity, and abnormal immune function. The previous research results show that tetrahedral framework nucleic acids (tFNAs), a new type of nanomaterial, can promote various biological activities of cells, such as cell proliferation, migration, anti-inflammation and anti-oxidation, and angiogenesis. Therefore, we intend to explore the potential of tFNAs in the treatment of BRONJ through this study. The results show that tFNAs can promote the treatment of BRONJ by promoting angiogenesis and promoting M2 polarization in macrophages and inhibiting M1 polarization both in vitro and in vivo. These results provide a theoretical basis for the application of tFNAs in the treatment of BRONJ and also provide new ideas and methods for the treatment of other diseases based on ischemia and immune disorders.

Zoledronic acid (ZA) is a bisphosphonate (BP) drug that has been widely used in clinical treatments as a potent bone resorption inhibitor. In recent years, an increasing number of cases of bisphosphonate-associated osteonecrosis of the jaw (BRONJ) have been reported. This is a severe maxillofacial complication characterized clinically by bone exposure, necrosis, pain, and halitosis. Its pathogenesis is still not clear, and there is no effective clinical treatment known. Therefore, prevention of BRONJ is especially important. To provide a new research direction for the treatment of BRONJ, this study used a new tetrahedral framework nucleic acid (TFNA), which can antagonize the inhibitory effect of ZA on the differentiation and maturation of osteoclasts (OCs). In vivo and in vitro experiments showed that TFNAs at a specific concentration exhibited no cytotoxicity and could reverse the inhibition of ZA on OC differentiation and maturation, effectively inhibiting the formation of BRONJ.

While the skin is considered the first line of defense in the human body, there are some vulnerabilities that render it susceptible to certain threats, which is an issue that is recognized by both patients and doctors. Cutaneous wound healing is a series of complex processes that involve many types of cells, such as fibroblasts and keratinocytes. This study showed that tetrahedral framework nucleic acids (tFNAs), a type of self-assembled nucleic-acid material, have the ability to promote keratinocyte(HaCaT cell line) and fibroblast(HSF cell line) proliferation and migration in vitro. In addition, tFNAs increased the secretion of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in HSF cells and reduced the production of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in HaCaT cells by activating the AKT-signaling pathway. During in vivo experiments, tFNA treatments accelerated the healing process in skin wounds and decreased the development of scars, compared with the control treatment that did not use tFNAs. This is the first study to demonstrate that nanophase materials with the biological features of nucleic acids accelerate the healing of cutaneous wounds and reduce scarring, which indicates the potential application of tFNAs in skin tissue regeneration.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a series of progressive motor disorders. PD is caused by dysfunction of basal ganglia, decrease of dopaminergic neurons in substantia nigra, and abnormal accumulation of Lewy bodies and Lewy neurites. Antiparkinsonian agents, which are currently used for treatment of PD, exhibit unsatisfactory effects on disease control. In recent years, tetrahedral framework nucleic acids (TFNAs) have been considered as multifunctional nanomaterials, and their scope of application has been extended to a wide range of areas. In previous studies, TFNAs were shown to exert positive effects on various cell types in processes such as cell proliferation, cell differentiation, and apoptosis. In the present study, we explored the role of TFNAs in the treatment and prevention of PD in vitro and elucidated its underlying mechanisms of action. On the basis of the experiments conducted, we demonstrated that TFNAs could inhibit and repair the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of PC12 cells through decreasing the accumulation of α-synuclein, one of the characteristic biomarkers of PD. Genes and proteins related to the AKT/PI3K signaling and mitochondrial apoptotic pathways were examined to further support this finding. Most importantly, TFNAs exhibited unexpected neuroprotective and neurorestorative effects on PC12 cells, providing a novel approach for reducing the neuropathological changes caused by PD.

Since its discovery in 1978, cisplatin‐based chemotherapy regimens have served a pivotal role in human cancer treatment, saving millions of lives. However, its high risk still poses a significant challenge for cisplatin‐induced acute kidney injury (AKI), which occurs in 30% of cisplatin‐treated patients. Unfortunately, no effective solution for preventing or managing this severe complication, which greatly impacts its clinical administration. Kidney is the main organ injured by cisplatin, and the injury is related to cisplatin‐induced cell apoptosis and DNA injury. Therefore, to achieve the safe use of cisplatin in tumour treatment, the key lies in identifying a kidney treatment that can effectively minimize cisplatin nephrotoxicity. Here, we successfully synthesized and applied a DNA‐nanostructure complex, named TFG, which contains tetrahedral framework nucleic acids (tFNAs) and FG‐4592, a novel Hif‐1α inducer. As cargo, TFG is composed entirely of DNA strands. It possesses low nephrotoxicity and renal aggregation properties while FG‐4592 is able to relieve renal injury by downregulating the apoptosis signal pathways. And it can relieve cisplatin‐induced renal injury when taken cisplatin treatment. This work aims to enhance chemotherapy protection in tumour patients by using TFG, a DNA‐based nanomedicines to kidney. This work has the potential to revolutionize the treatment of renal diseases, particularly drug‐induced kidney injury, leading to improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Nucleic acid therapy has played a promising role in the treatment of many diseases, such as cancer, infections, immune diseases, and neurodegenerative diseases. However, its application is still limited mainly because of poor cell-entry performance and low resistance to in vivo degradation. Tetrahedral framework nucleic acids (tFNAs) have shown potential in delivering low-molecular-weight drugs owing to their stability, biocompatibility, cell-entry performance, and flexible drug-loading ability. In particular, tFNAs can successfully deliver oligonucleotide drugs with improved effects and co-deliver oligonucleotide drugs with other drugs for synergistic effects. In this review, the recent progress on tFNA-based delivery of oligonucleotide drugs is outlined by single delivery systems—through sequence extension and complementation, and co-delivery systems—through multiple sequence extension, drug–DNA interactions, and specific binding. Furthermore, the current limitations and future developments of tFNA-based delivery of oligonucleotide drugs are discussed. [ABSTRACT FROM AUTHOR]

Objectives: To provide a new research direction for nerve regeneration and strategy for Alzheimer's disease treatment, tetrahedral DNA nanostructures (TDNs)—novel tetrahedral framework nucleic acid molecule nanoparticles (tFNA) that can inhibit the apoptosis of nerve cells are employed in the experiment. Materials and methods: To verify the successful preparation of TDNs, the morphology of TDNs was observed by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The expression of apoptosis‐related genes and proteins was investigated by confocal microscope, flow cytometry, PCR and Western blot to detect the impact of TDNs on the Alzheimer's model. And finally, Morris water maze experiment was used to test behavioural changes and Nissl stain was detected to observe the morphology and quantity of neurons in the hippocampus. Immunofluorescence stain was used to observe the Aβ stain, and TUNEL dyeing was utilized to observe neuronal apoptosis. Results: In vitro and in vivo experiments confirm that TDNs, in a specific concentration range, have no toxic or side effects on nerve cells, can effectively inhibit apoptosis in an Alzheimer's disease cell model and effectively improve memory and learning ability in a rat model of Alzheimer's disease. Conclusions: These findings suggest that TDNs may be a promising drug for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • MTX@Tapt-tFNAs, was developed to combine the dual roles of MTX and TNF-α-targeted DNA aptamer • MTX@Tapt-tFNAs show good biocompatibility, serum stability, targeting, and low toxicity. • MTX@Tapt-tFNAs exert a good anti-inflammatory effect by blocking TNF-α-NF-κB signaling and promoting M2 macrophage polarization. Rheumatoid arthritis (RA), a chronic autoimmune disease (AD), can cause irreversible loss of joint function. The methotrexate (MTX) is the first-line choice in the treatment of RA; however, its efficacy is limited due to its insolubility in water and lack of targeting ability. The development of nucleic acid nano system provides new prospect for it. Therefore, considering that tumor necrosis factor-α (TNF-α) is the cornerstone and significant target of ADs treatment, the TNF-α-targeted aptamer (Tapt)-modified tetrahedral frame nucleic acid (Tapt-tFNAs, TT) were chosen to carry MTX, which assembled into MTX-loaded Tapt-tFNA polyplexes (MTX@Tapt-tFNAs, MTT). As a carrier, tFNAs not only enhance the stability of Tapt in serum but strengthen the bioavailability of MTX. MTX@Tapt-tFNAs promote the expression of M2 macrophages and inhibit inflammatory factor infiltration by blocking the nuclear factor-κB (NF-κB) and extracellular regulated protein kinases (ERKs) signaling pathways. Moreover, MTX@Tapt-tFNAs are more concentrated in the inflammatory joints to reduce toxicity caused by systemic use of MTX, decrease collagen-induced arthritis (CIA) lesions and bone and cartilage defects. These results indicate that MTX@Tapt-tFNAs are a promising targeted nanomedicine against RA. [ABSTRACT FROM AUTHOR]