No abstract

Rapid and efficient tools for early cancer detection have diagnostic and therapeutic value. Given that the DNA hairpin-based hybridization chain reaction (HCR) is effective in detecting various biological targets, a tetrahedral framework DNA-enhanced (TDN-enhanced) HCR detection system (T-probe system) is introduced for cancer-related targets and its versatility is demonstrated by detecting intracellular target miRNA 21 and cellular membrane target nucleolin. Benefiting from the spatial confinement of the TDN, the T-probe system demonstrates a high detection rate. It increases the reaction efficiency of nude hairpins in vitro while accurately and rapidly recognizing both membrane and intracellular cancer-related targets in living cells. Furthermore, it exhibits superior fluorescence in vivo within 15 s of peripheral-tumor injection and 10 min of tail-vein injection. The T-probe system efficiently and accurately images tumor-related biomarkers in vitro and in vivo, thereby demonstrating great potential for clinical diagnosis and therapeutic applications.

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.

Ischemic stroke is a main cause of cognitive neurological deficits and disability worldwide due to a plethora of neuronal apoptosis. Unfortunately, numerous neuroprotectants for neurons have failed because of biological toxicity, severe side effects, and poor efficacy. Tetrahedral framework nucleic acids (tFNAs) possess excellent biocompatibility and various biological functions. Here, we tested the efficacy of a tFNA for providing neuroprotection against neuronal apoptosis in ischemic stroke. The tFNA prevented apoptosis of neurons (SHSY-5Y cells) caused by oxygen-glucose deprivation/reoxygenation through interfering with ischemia cascades (excitotoxicity and oxidative stress) in vitro. It effectively ameliorated the microenvironment of the ischemic hemisphere by upregulating expression of erythropoietin and inhibiting inflammation, which reversed neuronal loss, alleviated cell apoptosis, significantly shrank the infarction volume from 33.9% to 2.7%, and attenuated neurological deficits in transient middle cerebral artery occlusion (tMCAo) rat models in vivo. In addition, blocking the TLR2-MyD88-NF-κB signaling pathway is a potential mechanism of the neuroprotection by tFNA in ischemic stroke. These findings indicate that tFNA is a safe pleiotropic nanoneuroprotectant and a promising therapeutic strategy for ischemic stroke.

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.

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.

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.

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.