Diabetes is one of the most common endocrine and metabolic diseases, affecting around 537 million people nowadays, and this number may increase to 643 million by 2030 (11.3% of the global population) . Among different categories, T1DM is mainly resulted from an autoimmune process, in which the body’s immune system attacks the insulin-producing β-cells of the pancreas, posing a great challenge to prevent the disease. Although it may develop at any age, T1DM mainly affects children and adolescents (1.2 million cases in 2021), accounting for approximate 90% of all types of childhood diabetes [2, 3]. In recent years, the incidence of T1DM has increased significantly by 2–5% worldwide, arousing urgent social and medical worry and concern to the whole population [2, 4]. Without prompt and effective treatment, T1DM patients may readily lose blood sugar control, leading to acute ketoacidosis and severe hypoglycemia, as well as complications including heart disease, kidney failure or blindness . T1DM is believed to be a multifactorial consequence all along, however, there is overwhelming evidence that it is an autoimmune disease, typically mediated by an autoreactive T cell, characterized by a progressive immune destruction of insulin-producing β cells in the pancreatic islets, and subsequently resulting in absolute insulin deficiency and hyperglycemia within patients [5–8]. In this case, to date, insulin replacement therapy is the mainstay for T1DM treatment. Nevertheless, due to such inconvenience as lifelong insulin injection, poor compliance of young patients, long-term blood glucose monitoring and repeat health seeking, T1DM has brought a serious burden to the life, economy and emotion of patients and their family members [9, 10].
In the past few decades, numerous studies have been conducted to identify the causative factors of the T1DM with the aim of further discovering treatments or prevention in avoiding symptoms . However, the etiology of T1DM has not yet been fully illustrated owing to multifactorial involvement . On the basis of current knowledge, T1DM is considered to be an autoimmune disease resulting from a series of genetic, immunologic and environmental factors . Self-antigens are processed by dendritic cells (DCs) and macrophages, presented in the form of antigenic peptide-loaded with major histocompatibility complex II (MHC-II) and then activate CD4+ T cells, which return to the islet β cells, recruit cytotoxic T cells and other inflammatory cells. IL-12 (Interleukin-12) secreted by activated DCs and macrophages stimulate the Th1 (T helper 1) cells releasing cytokines such as interferon-γ, IL-2 and TNF-α (tumor necrosis factor, TNF), etc., concurrently inhibit Th2 cells to secrete IL4, IL-5 and IL-10 etc., which further lead to cytotoxic T cells, macrophages and NKs (natural killer cell, NK) activation and ultimately islet β cells damage [5, 8]. The ensuing insulin deficiency and hyperglycemia require alternative exogenous insulin injections, which however cannot hold up the progression of autoimmune response and the life expectancy shortening of T1DM patients with complications [13, 14]. Therefore, this has greatly inspired scientists and doctors to develop various technical methods for etiological prevention or treatment of the T1DM, especially in aspects of immune therapy [15–17].
Notably, a variety of immunotherapies have been applied in clinical studies for T1DM therapy and brought great hope to the patients, such as immune-suppressants, immune-modulators, induction of immune tolerance and immunological intervention targeting genes [18, 19]. Yet so, facing the heterogeneity of type 1 diabetes, diversity of islet antigens and complexity of autoimmune processes, sufficient success has rarely been achieved to completely halt or reverse the progression of type 1 diabetes, and meanwhile, its safety, high price, ethical issues and long-term efficacy remain controversial [20–23]. The “hygiene hypothesis” proposed that improvement of sanitation and infrequent exposure of children to infections are the main triggers for the rise in autoimmune disorders, which was notable in the most significant increase in T1DM incidence in industrialized societies with decreasing exposure to parasites [24, 25]. Numerous evidence supported the potential efficacy of helminth infections and helminth derivatives in treating the T1DM mouse model [26–30]. Schistosomiasis infection and exposure to schistosoma-derived antigens have been shown to prevent Th1-mediated autoimmune diseases including T1DM, multiplesclerosis (MS) and Crohn's disease [31, 32]. It was reported that Schistosoma mansoni infection or its adult/egg antigens are able to decrease the incidence of T1DM in rodents, and similar results were investigated in a broad spectrum of studies in other T1DM animal models with Schistosoma japonicum infection [31, 33–35]. T1DM has proven to be an autoimmune disease mainly mediated by Th1 cells, while Schistosoma spp. infection leads to the polarization of Th2 type immune response, thus weakening the activity of Th1 cells and arresting the occurrence or development of T1DM [36, 37]. As a co-evolving pathogen with humans, parasites regulate host immune responses and build up an anti-inflammatory microenvironment, which might provide a new strategy for the prevention and treatment of T1DM.
Most studies have been limited to living worm infection or crude worm proteins obtained from animal models, and the use of purified derivatives or proteins may not necessarily produce immunomodulatory effects similar to those induced by intact worm antigens in the host, and may not achieve desirable effects [34, 35, 38]. At the same time, the inevitable side effects caused by worm proteins, the safety of living worm infection and the rejection of patients make it difficult to accept parasites ethically. Hence parasite products are not considered for clinical application. To address the challenge of the immunotherapy of parasite-related products in T1DM, based on our previous success in microneedle-based strategies [39–43], herein we develop an asymmetric microneedle patch for the continuous and safe release of inactivated Schistosoma japonicum eggs. Microneedles are micron-sized needle-shaped structures that can penetrate the stratum corneum of the skin with a thumb press or an applicator to deliver drugs in a minimally invasive and painless way , which would significantly improve patient’s compliance. Conventional microneedle usually remains the patch base on the skin surface for a long time, triggering severe discomfort to the patient and posing a high infection risk [45, 46]. Moreover, aiming to continuously mediate the immune-response of the host, the microneedles are required to sustained release the payload locally, allowing more chance for the released active components to interact with local dendritic cells and antigen-presenting cells [47, 48].
Given these challenges, we developed a Schistosoma japonicum egg tip-loaded asymmetric microneedle (STAMP), in which the base layer was designed as an easy-fracture structure (an imperfection on one side) and fixed only within the epidermis layers of the skin. The isolated microneedles were then biodegraded slowly in the skin with sustained release and topical delivery of encapsulated eggs immobilized in the epidermal layer of the skin for at least 2 weeks to well regulate the releasing amount of eggs and ensure the localization and safety of antigen stimulation. Intriguingly, the results indicated that the STAMP could effectively control blood glucose level and ameliorate the degree of pancreatic lesions in T1DM mice. Notably, different from other immunotherapy, the adjuvant seems to be not necessary in this system, possibly ascribing to the fact that the intact egg contains sufficient immunomodulatory components, simplifying the formulation preparation. Based on the results, we believe that the STAMP has exhibited the promising potential to serve as an efficient strategy to combat T1DM by providing long-lasting effects to prevent islet destruction of patients and reduce the occurrence of complications. This technique opens a new window in immunotherapy and may be utilized in other autoimmune diseases in the near future.