Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.

Resistance to traditional antiepileptic drugs is a major challenge in chronic epilepsy treatment. MicroRNA-based gene therapy is a promising alternative but has demonstrated limited efficacy due to poor blood-brain barrier permeability, cellular uptake, and targeting efficiency. Adenosine is an endogenous antiseizure agent deficient in the epileptic brain due to elevated adenosine kinase (ADK) activity in reactive A1 astrocytes. We designed a nucleic acid nanoantiepileptic drug (tFNA-ADKASO@AS1) based on a tetrahedral framework nucleic acid (tFNA), carrying an antisense oligonucleotide targeting ADK (ADKASO) and A1 astrocyte-targeted peptide (AS1). This tFNA-ADKASO@AS1 construct effectively reduced brain ADK, increased brain adenosine, mitigated aberrant mossy fiber sprouting, and reduced the recurrent spontaneous epileptic spike frequency in a mouse model of chronic temporal lobe epilepsy. Further, the treatment did not induce any neurotoxicity or major organ damage. This work provides proof-of-concept for a novel antiepileptic drug delivery strategy and for endogenous adenosine as a promising target for gene-based modulation.

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.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer, and it has aggressive and more frequent tissue metastases than other breast cancer subtypes. Because the proliferation of TNBC tumor cells does not depend on estrogen receptor (ER), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2) and lacks accurate drug targets, conventional chemotherapy is challenging to be effective, and adverse reactions are severe. At present, the treatment strategy for TNBC generally depends on a combination of surgery, radiotherapy, and chemotherapy. Conventional administration methods have minimal effects on TNBC and cause severe damage to normal tissues. Therefore, it is an urgent task to develop an efficient and practical way of drug delivery and open up a new horizon of targeted therapy for TNBC. In our work, bovine serum albumin (BSA) acted as the protective film to prolong the circulation time of the tetrahedral framework nucleic acid (tFNA) delivery system and resist immune clearance in vivo. tFNA was used as a carrier loaded with DOX and AS1411 aptamers for the targeted treatment of triple-negative breast cancer. Compared with existing approaches, this optimized system exhibits stronger tumor-targeting so that tFNAs can be more concentrated around the tumor tissue, reducing DOX toxicity to other organs. This bionic delivery system exhibited effective tumor growth inhibition in the TNBC mice model, offering the clinical potential to promote the treatment of TNBC with great potential for clinical translation.

The skin is the first line of defense for the human body and is vulnerable to injury. Various topical or systemic diseases facilitate skin inflammation, and when the intensity or duration of skin injury exceeds the ability of tissue repair, fibrosis, an outcome of a dysregulated tissue-repair response, begins to dominate the repair process. However, existing methods for reducing skin fibrosis are insufficient and cause side effects, highlighting the need for drugs that effectively inhibit skin fibrosis and reduce immunogenicity, inflammation, apoptosis, and pyroptosis. Tetrahedral framework nucleic acids (tFNAs) are DNA nanomaterials that have a unique spatial structure, demonstrate excellent biosecurity, and promote anti-inflammatory, antioxidative, antifibrotic, angiogenic, and skin-wound-healing activities with almost no toxicity. Here, we explored the potential of tFNAs in skin fibrosis therapy in vitro and in vivo. After incubating cells or injecting mice with profibrogenic molecules and tFNAs, we found that the tFNAs inhibited the epithelial-mesenchymal transition, reduced inflammatory factor levels, decreased skin collagen content, and inhibited the pyroptosis pathway. These findings suggest the potential of tFNAs in treating pyroptosis-related diseases.

Choroidal neovascularization (CNV) is a common pathological feature of various eye diseases and an important cause of visual impairment in middle-aged and elderly patients. In previous studies, tetrahedral framework nucleic acids (tFNAs) showed good carrier performance. In this experiment, we developed microRNA-155-equipped tFNAs (T-155) and explored its biological effects on CNV. Based on the results of in-vitro experiments, T-155 could regulate macrophages into the antiangiogenic M1 type. Then, we injected T-155 into the vitreous of laser-induced CNV model mice and found that T-155 significantly reduced the size and area of CNV, inhibited blood vessel leakage. In summary, we prove that T-155 could regulate the inflammatory process of CNV by polarizing macrophages, thereby improving the symptoms of CNV. Thus, T-155 might become a new DNA-based drug with great potential for treating CNV.

More than 15 million out of 70 million patients worldwide do not respond to available antiepilepticus drugs (AEDs). With the emergence of nanomedicine, nanomaterials are increasingly being used to treat many diseases. Here, we report that tetrahedral framework nucleic acid (tFNA), an assembled nucleic acid nanoparticle, showed an excellent ability to the cross blood-brain barrier (BBB) to inhibit M1 microglial activation and A1 reactive astrogliosis in the hippocampus of mice after status epilepticus. Furthermore, tFNA inhibited the downregulation of glutamine synthetase by alleviating oxidative stress in reactive astrocytes and subsequently reduced glutamate accumulation and glutamate-mediated neuronal hyperexcitability. Meanwhile, tFNA promotes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization in the postsynaptic membrane by regulating AMPAR endocytosis, which contributed to reduced calcium influx and ultimately reduced hyperexcitability and spontaneous epilepticus spike frequencies. These findings demonstrated tFNA as a potential AED and that nucleic acid material may be a new direction for the treatment of epilepsy.

Tetrahedral framework nucleic acid (tFNA), a special DNA nanodevice, is widely applied in diverse biomedical fields. Due to its high programmability, biocompatibility, tissue permeability as well as its capacity for cell proliferation and differentiation, tFNA presents a powerful tool that could overcome potential barriers in the treatment of neurological disorders. This review evaluates recent studies on the use and progress of tFNA-based nanomaterials in neurological disorders.

Strategies for functionalizing diverse tetrahedral framework nucleic acids (tFNAs) have been extensively explored since the first successful fabrication of tFNA by Turberfield. One-pot annealing of at least four DNA single strands is the most common method to prepare tFNA, as it optimizes the cost, yield, and speed of assembly. This review concentrates on four key merits of tFNAs and their potential for biomedical applications. The natural ability of tFNA to scavenge reactive oxygen species, along with remarkable enhancement in cellular endocytosis and tissue permeability based on its appropriate size and geometry, promotes cell-material interaction to direct or probe cell behavior, especially to treat inflammatory and degenerative diseases. Moreover, the structural programmability of tFNA enables the development of static tFNA-based nanomaterials via engineering of functional oligonucleotides or therapeutic molecules, and dynamic tFNAs via attachment of stimuli-responsive DNA apparatuses, leading to potentially applications in targeted therapies, tissue regeneration, antitumor strategies, and antibacterial treatment. Although there are impressive performance and significant progress, challenges and prospects of functionalizing tFNA-based nanostructures are still indicated in this review. This article is protected by copyright. All rights reserved.

Articular cartilage (AC) injury repair has always been a difficult problem for clinicians and researchers. Recently, a promising therapy based on mesenchymal stem cells (MSCs) has been developed for the regeneration of cartilage defects. As endogenous articular stem cells, synovial MSCs (SMSCs) possess strong chondrogenic differentiation ability and articular specificity. In this study, a cartilage regenerative system was developed based on a chitosan (CS) hydrogel/3D-printed poly(ε-caprolactone) (PCL) hybrid containing SMSCs and recruiting tetrahedral framework nucleic acid (TFNA) injected into the articular cavity. TFNA, which is a promising DNA nanomaterial for improving the regenerative microenvironment, could be taken up into SMSCs and promoted the proliferation and chondrogenic differentiation of SMSCs. CS, as a cationic polysaccharide, can bind to DNA through electrostatic action and recruit free TFNA after articular cavity injection in vivo. The 3D-printed PCL scaffold provided basic mechanical support, and TFNA provided a good microenvironment for the proliferation and chondrogenic differentiation of the delivered SMSCs and promoted cartilage regeneration, thus greatly improving the repair of cartilage defects. In conclusion, this study confirmed that a CS hydrogel/3D-printed PCL hybrid scaffold containing SMSCs could be a promising strategy for cartilage regeneration based on chitosan-directed TFNA recruitment and TFNA-enhanced cell proliferation and chondrogenesis.