Colitis, a form of inflammatory bowel disease (IBD) characterized by inflammation of the colon, has significant clinical and epidemiological relevance and affects millions of people worldwide. From a clinical perspective, colitis manifests with symptoms such as abdominal pain, diarrhea, rectal bleeding, and weight loss. The exact cause of colitis remains unknown; however, it is believed to result from a combination of genetic predisposition, environmental factors, and immune system dysregulation [8].

The immune system plays a vital role in maintaining intestinal homeostasis by regulating inflammatory responses and promoting tolerance toward the gut microbiota [5]. In colitis, this delicate balance is disturbed, leading to an excessive immune response against commensal gut bacteria. This dysregulated immunity causes chronic inflammation, tissue injury, and the hallmark symptoms of colitis [27]. Tregs are a specialized subset of T cells that play a central role in maintaining peripheral immune tolerance and controlling excessive immune responses. These cells express the transcription factor Foxp3 and function to suppress effector T cells and other immune cells involved in inflammatory processes [25]. Several studies have shown that enhancing Treg function or expanding their population can alleviate colitis symptoms and decrease intestinal inflammation [6], [14]. This has led to the exploration of various therapeutic strategies aimed at Tregs, including adoptive Treg transfer, modulation of Treg function using immunomodulatory drugs, and manipulation of the gut microbiota to enhance Treg expansion [7], [9], [19].

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of neutrophils and monocytes that possess immunosuppressive properties and are typically associated with pathological conditions such as cancer. However, their roles in physiological processes such as pregnancy and fetal development have also been elucidated. There have been numerous attempts to harness MDSCs in models of immunopathology regarding their immunomodulatory properties [20]. However, the use of cell-based therapies is associated with challenges, including ethical concerns, the requirement for specialized facilities, the risk of alloimmune responses, and limited compatibility with conventional therapeutic platforms [17]. One of the promising alternatives to cell therapies is cell-derived extracellular vesicles (EVs). EVs are membrane-bound particles that, when in the double-membraned form and measuring 30–150 nm, originate from the inward budding of endosomal membranes and are referred to as exosomes [28]. EVs can carry a wide range of cargoes which are provided from the cell of origin. They contain various bioactive molecules, including proteins, lipids, and nucleic acids. These EVs can mediate intercellular communication and transfer their cargo to target cells, thereby influencing cellular functions and behaviors [4], [26]. EVs can be isolated from a variety of sources, including cell culture supernatants, making them more accessible than the parent cells. There are also several therapeutic exploitations from EVs and exosomes in experimental models of cancer, infection, neurological, immunological diseases [10], [11], [12], [24]. In the case of MDSCs, the immunomodulatory properties of their exosomes have been demonstrated in models of autoimmune diseases, such as alopecia areata and arthritis [33], [34].

However, their impact on distinct aspects of IBD such as immunological profile, histopathology, and gut microbiome remained to be elucidated. Regarding the immunomodulatory effects of MDSC-derived EVs and the contribution of immune dysregulation to colitis pathophysiology, this study aimed to assess the effects of G-MDSC-derived EVs on various aspects of colitis pathology in a murine model of dextran sulfate sodium (DSS)-induced colitis.