近年来1型糖尿病（type 1 diabetes, T1D）的发病率迅速增加，尤其是在儿童和年轻人中，呈现出年轻化趋势。目前，胰岛素仍是T1D最主要的临床治疗方法，然而胰岛素并不能阻止T1D的进一步恶化。大量研究提出抗原特异性免疫耐受诱导是一种具有潜力的预防或延缓T1D进程的免疫治疗方法，然而临床试验中，接种单一T1D自身抗原诱导免疫耐受的免疫治疗方式几乎无法对T1D产生治疗效果。超分子水凝胶肽因其具有既可作为抗原自身诱导免疫效应，同时还能作为免疫佐剂改善效价的出色能力，在疫苗开发、药物递送、免疫调节领域显示出巨大的潜力。先前的报道已经证明了非甾体抗炎药萘乙酸修饰的D构型四肽谷氨酸-苯丙氨酸-苯丙氨酸-酪氨酸（glutamate-phenylalanine-phenylalanine-tyrosine, GFFY）超分子水凝胶肽（naphthylacetic acid modified D-tetrapeptide of GFFY, Nap-G^DF^DF^DY）是一类兼备抗原免疫刺激作用的优秀肽类疫苗佐剂。本研究发现GFFY在多种物种的T1D主要自身抗原胰岛素、胰岛素原和谷氨酸脱羧酶（glutamic acid decarboxylase, GAD）中高度保守。考虑到基于胰岛素肽段GFFY的超分子水凝胶肽可能通过模拟多种T1D自身抗原的结构和功能发挥诱导T1D免疫耐受的作用，本研究探究了使用超分子水凝胶肽的抗原特异性免疫调节方法治疗T1D的可能性。本研究发现，在接种Nap-G^DF^DF^DY后，非肥胖糖尿病（nonobese diabetic, NOD）小鼠（T1D模型小鼠）可以完全预防并避免遭受T1D危害直至36周龄，同时可观察到，经Nap-G^DF^DF^DY处理后的小鼠胰腺内胰岛形态保持得更加完好，胰岛中免疫细胞浸润最少，并且胰岛内胰岛素分泌细胞（β细胞）遭遇去分化的情况最弱。进一步研究发现，Nap-G^DF^DF^DY对胰岛的保护功能主要归因于其对外周调节性T细胞（regulatory T cells, Tregs）增殖的促进作用，具体表现为脾脏Tregs百分比含量的增加，此外Nap-G^DF^DF^DY还能维持Tregs对TGF-β1等的分泌功能的稳定性。对小鼠血清中细胞因子进行细胞因子芯片微阵列（cytokine chip microarray）检测后发现Nap-G^DF^DF^DY对NOD小鼠全身炎症反应具有“缓冲”作用。综上可得，Nap-G^DF^DF^DY可通过免疫调控，有效延缓NOD小鼠中T1D发病所引起的血糖升高。鉴于Nap-G^DF^DF^DY具有优良的T1D预防能力，并同时兼备佐剂的通用性和出色的辅助效力，我们提出Nap-G^DF^DF^DY或可成为T1D免疫耐受诱导治疗策略中具有临床潜力的新型治疗手段。

In recent years, the incidence of type 1 diabetes (T1D) has increased, substantially especially among children and young adults. Morbidity of T1D also shows a concerning tendency of getting younger. At present, insulin replacement therapy is still the most commonly used clinical method for treating T1D. However, insulin have no effect on preventing the further deterioration of T1D. Extensive studies have reported that antigen-specific immune tolerance induction could be a feasible and effective way to prevent or delay the progression of T1D. Nonetheless, inoculation with single T1D autoantigen had been associated with poor clinical outcome. Supramolecular hydrogel based on peptide can self-assemble into various micro- or nano-structures, and have shown promising potential in vaccine development, controlled drug delivery and immune regulation. Previous reports have elucidated that these peptide nanoclusters have the ability to function both as antigen depot and immune adjuvant. Recent research on cancer immunotherapy development have revealed the therapeutic potential of Nap-G^DF^DF^DY, a naphthylacetic acid modified D-isomer tetrapeptide of glutamate-phenylalanine-phenylalanine-tyrosine (GFFY) hydrogel, as a kind of excellent vaccine adjuvant. Inadvertently, we have found that Nap-G^DF^DF^DY contain conserved peptide sequence, GFFY, of 3 major autoantigens for autoimmune T1D, i.e. insulin, proinsulin, and glutamic acid decarboxylase (GAD). Considering that insulin peptide GFFY-based supramolecular hydrogel may potentially simulate the structure and function of multiple major autoantigens of T1D, this study investigated the possibility of supramolecular hydrogel peptide as a promising treatment of T1D for antigen-specific immune tolerance induction. Subsequently, by using Nap-G^DF^DF^DY as immune therapy against T1D, our data showed that subcutaneous injection of Nap-G^DF^DF^DY achieved complete protection of nonobese diabetic (NOD) mice from T1D development till the age of 36 weeks. Pancreatic islet morphology was better maintained with minimal immune cell infiltration and significantly alleviated dedifferentiation of islet β cells in NOD mice treated with Nap-G^DF^DF^DY. Preliminary evidence indicated that the protective role of Nap-G^DF^DF^DY is likely attributable to its positive impact on increased peripheral T regulatory cells (Tregs) population and maintained the function of Tregs including the secretion of TGF-β1, etc. Serum cytokine microarray result further implicated a “buffering” role of Nap-G^DF^DF^DY in systemic inflammatory tone in NOD mice. Our studies on NOD mice that were already hyperglycemia futher demonstrated that Nap-G^DF^DF^DY can effectively delay the increase in blood sugar caused by T1D. These findings indicated positive effects of Nap-G^DF^DF^DY in T1D prevention. We propose that Nap-G^DF^DF^DY could be a novel immune therapeutic intervention strategy for T1D.