Tetrahedral Framework Nucleic Acids Reverse New-Onset Type 1 Diabetes.
2021
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.
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