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Astrocytes, as the most plentiful subtypes of glial cells, play an essential biphasic function in ischemic stroke (IS). However, although having beneficial effects on stroke via promoting nerve restoration and limiting lesion extension, astrocytes can unavoidably cause exacerbated brain damage due to their participation in the inflammatory response. Therefore, seeking an effective and safe drug/strategy for protecting and regulating astrocytes in stroke is urgent. Here, we employ tetrahedral framework nucleic acid (tFNA) nanomaterials for astrocytes in stroke, considering their excellent biological properties and outstanding biosafety. In vitro, tFNA can inhibit calcium overload and ROS regeneration triggered by oxygen-glucose deprivation/reoxygenation (OGD/R), which provides a protective effect against astrocytic apoptosis. Furthermore, morphological changes such as hyperplasia and hypertrophy of reactive astrocytes are restrained, and the astrocytic polarization from the proinflammatory A1 phenotype to the neuroprotective A2 phenotype is facilitated by tFNA, which further alleviates cerebral infarct volume and facilitates the recovery of neurological function in transient middle cerebral artery occlusion (tMCAo) rat models. Moreover, the TLRs/NF-κB signaling pathway is downregulated by tFNA, which may be the potential mechanism of tFNA for protecting astrocytes in stroke. Collectively, we demonstrate that tFNA can effectively mediate astrocytic apoptosis, activation, and polarization to alleviate brain injury, which represents a potential intervention strategy for IS.

Background: Nucleic acid is a genetic material that shows great potential in a variety of biological applications. With the help of nanotechnology, the fabrication of DNA-based nanomaterials has emerged. From genetic DNA to non-genetic functional DNA, from single-layer and flat structure to multi-layer and complex structure, and from two-dimensional to three-dimensional structure, DNA-based nanomaterials have been greatly developed, bringing significant changes to our lives. In recent years, the research of DNA-based nanomaterials for biological applications has developed rapidly. Methods: We extensively searched the bibliographic database for a research article on nanotechnology and immunotherapy and further discussed the advantages and drawbacks of current DNA-based nanomaterials in immunotherapy. By comparing DNA-based nanomaterials with traditional biomaterials applied in immunotherapy, we found that DNAbased nanomaterials are a promising candidate material in Immunotherapy. Results: Due to the unrivaled editability and biocompatibility, DNA-based nanomaterials are not only investigated as therapeutic particles to influence cell behavior but also as drug delivery systems to treat a variety of diseases. Moreover, when DNA-based nanomaterials are loaded with therapeutic agents, including chemical drugs and biomolecules, which significantly enhance the therapeutic effects, DNA-based nanomaterials have great potential in immunotherapy. Conclusion: This review summarizes the structural development history of DNA-based nanomaterials and their biological applications in immunotherapy, including the potential treatment of cancer, autoimmune diseases, and inflammatory diseases.

This study aimed to introduce a minimally invasive technique for maxillary sinus floor elevation using the lateral approach (lSFE) and to determine the factors that influence the stability of the grafted area in the sinus cavity. Thirty patients (30 implants) treated with lSFE using minimally invasive techniques from 2015 to 2019 were included in the study. Five aspects of the implant (central, mesial, distal, buccal, and palatal bone heights [BHs]) were measured using cone-beam computed tomography (CBCT) before implant surgery, immediately after surgery (T0), 6 months after surgery (T1), and at the last follow-up visit (T2). Patient characteristics were collected. A small bone window (height, 4.40 ± 0.74 mm; length, 6.26 ± 1.03 mm) was prepared. No implant failed during the follow-up period (3.67 ± 1.75 years). Three of the 30 implants exhibited perforations. Changes in BH, defined as the distance between the implant platform level and the uppermost level of bone graft, of the five aspects of implants showed strong correlations with each other and decreased dramatically before second-stage surgery. RBH did not significantly influence BH changes, whereas smoking status and type of bone graft material were potentially influential factors. During the 3-year observation period, lSFE with a minimally invasive technique demonstrated high implant survival and limited bone reduction in grafted area. In conclusion, patients who were nonsmoker and whose sinus cavity was filled with deproteinized bovine bone mineral (DBBM) had significantly limited bone resorption in grafted area.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas accompanied by tissue injury and necrosis. It not only affects the pancreas but also triggers a systemic inflammatory response that leads to multiorgan failure or even death. Moreover, there is no effective treatment currently that can reverse the disease progression. In this study, tetrahedral framework nucleic acids (tFNAs) were utilized to treat SAP in mice for the first time and proved to be effective in suppressing inflammation and preventing pathological cell death. Serum levels of pancreatitis-related biomarkers witnessed significant changes after tFNAs treatment. Reduction in the expression of certain cytokines involved in local and systemic inflammatory response were observed, together with alteration in proteins related to cell death and apoptosis. Collectively, our results demonstrate that tFNAs could both alleviate SAP and its subsequent multiorgan injury in mice, thus offering a novel and effective option to deal with SAP in the future.

Insulin resistance (IR) is one of the essential conditions in the development of type 2 diabetes mellitus (T2DM). IR occurs in hepatic cells when the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway is downregulated; thus, activating this pathway can significantly improve insulin sensitivity and ameliorate T2DM. Tetrahedral framework nucleic acids (tFNAs), a DNA nanomaterial, are synthesized from four single-stranded DNA molecules. tFNAs possess excellent biocompatibility and good water solubility and stability. tFNAs can promote cell proliferation, cell autophagy, wound healing, and nerve regeneration by activating the PI3K/Akt pathway. Herein, we explore the effects and underlying mechanisms of tFNAs on IR. The results displayed that tFNAs could increase glucose uptake and ameliorate IR by activating the IRS-1/PI3K/Akt pathway in glucosamine (GlcN)-stimulated HepG2 cells. By employing a PI3K inhibitor, we confirmed that tFNAs reduce IR through the PI3K/Akt pathway. Moreover, tFNAs can promote hepatic cell proliferation and inhibit GlcN-induced cell apoptosis. In a T2DM mouse model, tFNAs reduce blood glucose levels and ameliorate hepatic IR via the PI3K/Akt pathway. Taken together, tFNAs can improve hepatic IR and alleviate T2DM through the PI3K/Akt pathway, making contribution to the potential application of tFNAs in T2DM.

Tetrahedral framework nucleic acids (tFNAs) have attracted extensive attention as drug nanocarriers because of their excellent cellular uptake. However, for oligonucleotide cargos, tFNA mainly acts as a static delivery platform generated via sticky-ended ligation. Here, inspired by the original stable space inside the tetrahedral scaffold, a dynamic lysosome-activated tFNA nanobox is fabricated for completely encapsulating a short interfering RNA (siRNA) of interest. The closed tetrahedral structure endows cargo siRNA with greater resistance against RNase and serum and enables solid integration with the vehicle during delivery. Moreover, the pH-responsive switch of nanobox allows the controlled release of siRNA upon entry into lysosomes at cell culture temperature. Based on protective loading and active unloading, an excellent silencing effect on the target tumor necrosis factor alpha (TNFα) gene is achieved in in vitro and in vivo experiments. Conclusively, the nanobox offers a dynamic pH-sensitive confinement delivery system for siRNA and can be an extendable strategy for other small RNA.

Type 1 diabetes (T1D) is caused by breakdowns of central and peripheral immune tolerance and destructions of insulin-producing β-cells. Conventional insulin injection cannot cure the disease. Regulatory immune cells, including regulatory T-cells (Tregs) and regulatory B-cells (Bregs), play critical roles in immune tolerance. Inducing regulatory immune cells to halt the progress of T1D and restore immune tolerance is the promising approach in T1D immunotherapy. Here, tetrahedral framework nucleic acids (tFNAs) were utilized to treat T1D in non-obese diabetic (NOD) mice. 250 nM tFNA treatment was adopted in the experiment to reverse hyperglycemia and protect insulin-secreting β-cells in diabetic NOD mice. In addition, 250 nM tFNA treatment could induce Tregs and Bregs and suppress helper T (Th)-cells in the pancreas. In the pancreas, cytokines, as a significant signal during CD4+ T-cell differentiation, directly direct the differentiation programs. Apart from cytokines directing the differentiation of T-cells, the signal transducer and activator of transcription (STAT) signal is strongly associated with T-cell differentiation and T1D progression. We demonstrated tFNA treatment inducing regulatory immune cells probably by increasing TGF-β levels and the STAT signal. To sum up, 250 nM tFNA treatment could protect the diabetic NOD mice from hyperglycemia and preserve the functions of β-cells by restoring peripheral immune tolerance. The possible mechanism of inducing immune tolerance was related to the STAT signal and cytokine changes in the pancreas. Moreover, immunoregulation capabilities of tFNAs were demonstrated in the experiment, which set the foundation of tFNAs participating in further antigen-specific immunotherapies.

As one of the most frequent autoimmune diseases, Sjogren's syndrome (SS) is characterized by overactive lymphocytic infiltration in the exocrine glands, with ensuing dry mouth and dry eyes. Unfortunately, so far, there are no appropriate therapies without causing overall immunosuppression. Tetrahedral framework nucleic acids (tFNAs) were regarded as promising nanoscale materials whose immunomodulatory capabilities have already been verified. Herein, we reveal, for the first time, that tFNAs were utilized to treat SS in female nonobese diabetic (NOD) mice, the animal model used for SS. We proved a 250 nM tFNA treatment was successful in suppressing inflammation and stimulating saliva secretion in NOD mice. Specialised proteins for the secretory function and structure of acinar cells in submandibular glands (SMGs) were restored. It has been the permanent goal for SS treatment to establish immune tolerance and stop disease development. Surprisingly, tFNA treatment guided T cells toward regulatory T cells (Tregs), while suppressing T helper (Th) cell responses. Th cells include Th1, Th17, and follicular helper T (Tfh) cells. Tregs are highly significant in immune tolerance. Inducing Tregs is a promising approach to reestablish immune tolerance. Comparable results were also observed in B cell responses. Reductions in the percentage of germinal center (GC) B cells and plasma cells were detected, and a marked increase in the percentage of regulatory B cells (Bregs) was also noticed. The mechanisms of inducing Tregs may associated with cytokine changes. Changes of T cell subsets, especially changes of Tfh, may influence the differentiation of B cells accordingly. Collectively, our results demonstrated the immunomodulatory capacities of tFNAs once again, which may provide a novel, safe, and effective option for the treatment of SS and other autoimmune diseases.

Insulin resistance (IR) is one of the essential conditions in the development of type 2 diabetes mellitus (T2DM). IR occurs in hepatic cells when the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway is downregulated; thus, activating this pathway can significantly improve insulin sensitivity and ameliorate T2DM. Tetrahedral framework nucleic acids (tFNAs), a DNA nanomaterial, are synthesized from four single-stranded DNA molecules. tFNAs possess excellent biocompatibility and good water solubility and stability. tFNAs can promote cell proliferation, cell autophagy, wound healing, and nerve regeneration by activating the PI3K/Akt pathway. Herein, we explore the effects and underlying mechanisms of tFNAs on IR. The results displayed that tFNAs could increase glucose uptake and ameliorate IR by activating the IRS-1/PI3K/Akt pathway in glucosamine (GlcN)-stimulated HepG2 cells. By employing a PI3K inhibitor, we confirmed that tFNAs reduce IR through the PI3K/Akt pathway. Moreover, tFNAs can promote hepatic cell proliferation and inhibit GlcN-induced cell apoptosis. In a T2DM mouse model, tFNAs reduce blood glucose levels and ameliorate hepatic IR

A failure in immune tolerance leads to autoimmune destruction of insulin-producing β-cells, leading to type 1 diabetes (T1D). Inhibiting autoreactive T cells and inducing regulatory T cells (Tregs) to re-establish immune tolerance are promising approaches to prevent the onset of T1D. Here, we investigated the ability of tetrahedral framework nucleic acids (tFNAs) to induce immune tolerance and prevent T1D in nonobese diabetic (NOD) mice. In prediabetic NOD mice, tFNAs treatment led to maintenance of normoglycemia and reduced incidence of diabetes. Moreover, the tFNAs (250 nM) treatment preserved the mass and function of β-cells, increased the frequency of Tregs, and suppressed autoreactive T cells, leading to immune tolerance. Collectively, our results demonstrate that tFNAs treatment aids glycemic control, provides β-cell protection, and prevents the onset of T1D in NOD mice by immunomodulation. These results highlight the potential of tFNAs for the prevention of autoimmune T1D.

Highlights Tetrahedral framework nucleic acid (tFNA)-based delivery of resveratrol (RSV) ameliorates the performance of RSV.tFNAs-RSV improve insulin sensitivity in high-fat diet-fed mice by promoting Treg and Th2 and suppressing Th1 and Th17, and switching macrophage from M1 to M2 phenotype both in vitro and in vivo. Supplementary Information The online version contains supplementary material available at 10.1007/s40820-021-00614-6., Obesity-induced insulin resistance is the hallmark of metabolic syndrome, and chronic, low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Current therapeutic approaches lack efficacy and immunomodulatory capacity. Thus, a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance. Here, we synthesized a tetrahedral framework nucleic acid (tFNA) nanoparticle that carried resveratrol (RSV) to inhibit tissue inflammation and improve insulin sensitivity in obese mice. The prepared nanoparticles, namely tFNAs-RSV, possessed the characteristics of simple synthesis, stable properties, good water solubility, and superior biocompatibility. The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy. In high-fat diet (HFD)-fed mice, the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status. tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages. As for adaptive immunity, the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg, leading to the alleviation of insulin resistance. Furthermore, this study is the first to demonstrate that tFNAs, a nucleic acid material, possess immunomodulatory capacity. Collectively, our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice, suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s40820-021-00614-6.