There are fungi in the human body that are known as normal flora (Prasad, 2007). This population of fungi is called fungal microbiota or mycobiota (Limon et al., 2017). Knowing these microbiotas, including mycobiota, is an important factor in host diseases and health (Limon et al., 2017). For many reasons, when the balance of these mycobiota is upset they can become a pathogen. Fungal diseases effect a quarter of the human population worldwide (Brown et al., 2012). However, while most of the fungal diseases are related to superficial skin conditions and can be treated locally, the systemic fungal infection could be so lethal (Brown et al., 2012; Vallabhaneni et al., 2016). These systemic fungal diseases usually occur because of diverse immune responses; especially in patients with immune system suppression (Pappas et al., 2018). There are lots of treatment option for systemic fungal diseases, but using them has limitations and usually brings poor outcomes (Scriven et al., 2017). It seems that one of the best choices to treat fungal diseases is reversing immune deficiency, which occurs in patients with immunosuppression (Scriven et al., 2017).

A previous study on C. albicans revealed that the host immune response to C. albicans is downregulated at early stages by pathogenic fungi (Halder et al., 2020). It was shown that the C. albicans attached to the C3 receptor of the monocytes by its β-glucan. Using this attachment to the monocytes, the fungi stimulate the monocytes to release extracellular vesicles contained transforming growth factor (TGF)-β. Using TGF-β-transporting vesicles, the fungi reduce immune response and cause anti-inflammatory effects at the early stages of fungi pathogenesis (Halder et al., 2020). Moreover, using TGF-β production, the fungi could reduce early production and induction of pro-inflammatory cytokines (Netea et al., 2002; Halder et al., 2020). This is how the fungi downregulate the host immune system in order to favor its existence and survival.

The MSCs are the progenitor/stem cells that have the capacity to differentiate into multilineage cells (Billing et al., 2016; de Castro et al., 2019). Due to their potential for differentiation, their immunomodulatory effect, and their regeneration capacity (Zhang et al., 2020a; Oh et al., 2021), they are widely used in treating injuries and some inflammatory disorders (Zhang et al., 2020a; Liao et al., 2021). Clinical studies have shown that because of the immunomodulatory function of some subsets of MSCs, MSC therapy could suppress the immune system and treat inflammatory and autoimmune diseases (Nauta and Fibbe, 2007; Yang et al., 2013). In detail, the MSCs, directly or indirectly, affect T cells and regulate them. The MSCs produce some chemokines and cytokines such as interleukin 10 (IL-10), prostaglandin E₂ (PGE₂), nitric oxide (NO), TGF-β, indoleamine 2,3-dioxygenase (IDO), tumor necrosis factor-inducible gene 6 (TSG-6), and chemokine ligand 2 (Batten et al., 2006; Nauta and Fibbe, 2007; Yang et al., 2013). These molecules affect CD4⁺CD25⁺ regulatory T (T reg) with positive transcription factor Foxp3 and T helper 17 (Th17) cells' population and regulate them (Batten et al., 2006; Park et al., 2011; Yang et al., 2013; Bi et al., 2020). That's how MSCs downregulate the immune system in inflammatory and autoimmune diseases.

However, some previous studies have shown that another type of MSCs has an immune-stimulatory effect, and this variety of the biological functions of MSCs depends on Toll-like receptors (TLRs) (Figure 1) (Waterman et al., 2010; Yang et al., 2013). It was shown that engagement of TLR-4 could enhance the production of pro-inflammatory mediators such as IL-17 and these MSCs are called TLR4-primed MSCs (Figure 1) (Waterman et al., 2010; Yang et al., 2013). In contrast, it was shown that TLR3-primed MSCs act as an immunomodulatory subset of MSCs (Waterman et al., 2010; Yang et al., 2013). The TLR4-primed MSCs, in contrast with TLR3-primed MSCs, was shown to increase expression of IL-6 and IL-13 as a pro-inflammatory cytokine and decrease IL-4, IDO, and PGE₂ as an immunomodulatory cytokine and chemokine (Figure 1) (Waterman et al., 2010; Yang et al., 2013). IL-17 is a pro-inflammatory cytokine that plays a crucial role in intracellular and extracellular pathogenic defense (Yang et al., 2013; Schinocca et al., 2021). It was shown that a subpopulation of IL-17⁺ MSCs could inhibit C. albicans (Yang et al., 2013). Taken together, it might result that TLR4-primed and IL-17⁺ subsets of MSCs could be good candidates for fighting against fungal diseases (Figures 1, 2) (Waterman et al., 2010; Yang et al., 2013).

EVs have the main role in cell-to-cell communications (Andaloussi et al., 2013),and have been observed in both eukaryotes and prokaryotes (Ellis and Kuehn, 2010; Andaloussi et al., 2013). Studies have shown that the EVs could transfer the proteins and nucleic acids by its bilayer membrane (Lee et al., 2012; Ratajczak et al., 2012). Due to their potential for transferring proteins and nucleic acids, EVs are used widely as drug delivery agents (Elsharkasy et al., 2020). In order to best discuss the biological roles of EVs, here we describe the classification of EVs. The EVs based on their cellular origin, biological function, biogenesis, and size classified into three main groups: exosomes, microvesicles, and apoptotic bodies (Andaloussi et al., 2013; Yáñez et al., 2015). The two first particles, the exosomes and microvesicles, have been shown to have therapeutic effects (Wang et al., 2015; Phinney and Pittenger, 2017). The exosomes, with 40–120 nm in size, are generated by the endolysosomal pathway. In contrast with exosomes, the microvesicles are generated by budding from the cell surface (Andaloussi et al., 2013; Raposo and Stoorvogel, 2013). The exosomes with their non-sized particles, composed of a bilayer membrane and cytoplasm, contained mRNA, miRNA, and other RNAs' generated from the parent cell (Andaloussi et al., 2013; Raposo and Stoorvogel, 2013).

Stem cells, especially mesenchymal stem cells, were used widely in past decades as a candidate for therapies of various diseases. In recent years, exosome-derived stem cells were substitutionally used for regenerative and immune-therapy as a cell-free therapy (Ji et al., 2019; Qiu et al., 2020). Previous studies have shown that the exosome-derived stem cells contained various bioactive molecules, especially proteins and microRNAs which originated from maternal cells (Baharlooi et al., 2020; Ma et al., 2020). These exosomes were shown to have some biological effects inherited from their maternal cells (Baharlooi et al., 2020). For instance, the exosome-derived MSCs displayed angiogenesis, regeneration, and especially anti-inflammatory effects (Baharlooi et al., 2020). Moreover, it was shown that these exosomes could carry various cytokines and chemokines originated and produced by the maternal cell (Di Trapani et al., 2016; Baharlooi et al., 2020). So, here we can hypothesize that the TLR4-primed MSCs could pass their pro-inflammatory cytokines and chemokines into exosomes derived from them. Exosomes-derived TLR4-primed MSCs could trigger the host immune system to start inflammation against fungal pathogens and fight against the immunosuppressive path of fungi.