Infectious diseases have been a significant cause of morbidity and mortality worldwide; respiratory infections and pneumonia are among the major causes of global death (Sharma et al., 2021b). With the increasing number of outbreaks of new infectious diseases and the lack of effective treatments, it is crucial to identify new therapeutic strategies to combat infections and restore infection-related organ and tissue damage.

Mesenchymal stem cells (MSCs) are among the most commonly employed cell types in tissue repair and homeostasis, which have become an attractive therapeutic option for treating infectious diseases and disease-related tissue injury (Kashte et al., 2018; Kotas and Matthay, 2018). The effects of MSCs include anti-inflammatory properties, immunomodulatory capabilities, and regeneration (Fu et al., 2019). The efficacy of MSCs is mainly coming from the paracrine effect mediated by secreted growth factors, cytokines, and extracellular vesicles (EVs) (Liang et al., 2014; Paliwal et al., 2018).

MSC-derived extracellular vesicles (MSC-EVs) are identified to be the main components responsible for the paracrine effect. They transfer functional molecules, such as messenger RNA (mRNA), microRNA (miRNA), lipid, and protein, into tissue-specific cells that request repair (Taverna et al., 2017). Compared with MSCs, MSC-EVs possess hypoimmunogenic properties, have low tumorigenesis, and are more stable (Trounson and McDonald, 2015). In this mini-review, we briefly summarize the function of exosomes and discuss their potential role in therapeutic regimens in infectious diseases, including respiratory infections, sepsis, and intestinal infections in recent years.

Almost all cells, including MSCs, can secrete EVs due to intracellular vesicle sorting (Kourembanas, 2015). EVs are nano-sized spherical bio-membrane structures, which were previously divided into three main categories based on their size and biosynthesis: smaller-sized exosomes (30–100 nm) from the endocytic pathway, medium-sized microvesicles (MVs) (100–1,000 nm) from the cell plasma membrane shedding, and larger-sized apoptotic bodies (1,000–5,000 nm) from the apoptosis (Raposo and Stoorvogel, 2013). The endocytosis of the cell membrane may form early endosomes, which then develop into late endosomes, namely, multivesicular bodies (MVBs). MVBs either combine with lysosomes or be released as exosomes through exocytosis (Joo et al., 2020). In terms of MVs, they can be secreted directly by budding from the plasma membrane (Abbaszadeh et al., 2020) (Figure 1).

Assigning an EV to a particular biogenesis pathway remains extraordinarily difficult because of the absence of specific surface markers for three EV categories and the overlap in their physical size (Carnino et al., 2021). Therefore, guidelines set by the International Society for Extracellular Vesicles (ISEV) suggest considering the use of operational terms for EV subtypes that are based on: (a) physical characteristics of EVs, such as size [“small EVs” (< 200 nm) and “medium/large EVs” (> 200 nm)] or density (low, middle, high, with each range defined); (b) biochemical composition (CD63⁺/CD81⁺-EVs, Annexin A5-stained EVs, etc.); or (c) descriptions of conditions or cell of origin (podocyte EVs, hypoxic EVs, large oncosomes, apoptotic bodies) (Théry et al., 2018).

Over 80% of researchers chose differential ultracentrifugation for EVs isolation (Tkach and Théry, 2016). Traditional identification ways for EVs usually involve nanoparticle tracking analysis (NTA) for size information, transmission electron microscope (TEM) for morphological details, and Western blotting for membrane protein makers (Théry et al., 2018). Kim et al. (2019) recently developed an atomic force microscope-infrared spectroscopy (AFM-IR) approach to probe the structural composition of a single EV. Their protocol involves incubating the EV sample on a suitable substrate and setting up the AFM-IR instrument, as well as collecting nano-IR spectra and nano-IR images. Recorded IR spectra for EVs showed characteristic peaks at specific wavenumbers; it is possible to determine the presence of DNA (1,050–1,290 cm^–1), RNA (1,250–1,380 cm^–1), proteins (1,500–1,700 cm^–1), and phospholipids (1,000–1,250 cm^–1, 1,730–1,750 cm^–1, 2,800–3,000 cm^–1) (Kim et al., 2019) that may contribute to the understanding of EV biology and the development of EV therapies. This method could improve the understanding of EV biology and the development of EV therapies.

EVs secreted from MSCs can deliver many functional molecules such as mRNA, miRNA, lipids, and protein into recipient cells (Yin et al., 2019). These biological components are considered stable and can modulate cell behaviors in recipient cells. EVs use specific receptors or membrane fusion to enter recipient cells. Once EVs are absorbed, the biomolecules of EVs can regulate gene expression, essential enzyme reactions, signal cascade pathways, or other mechanisms in recipient cells (Ranghino et al., 2017). Thus, MSC-EVs can promote tissue regeneration by reprogramming several pathophysiological pathways such as immunomodulation, proliferation, apoptosis, angiogenesis, and oxidative (Grange et al., 2019a, b).

The function of EVs is mainly dependent on their source cells (Keshtkar et al., 2018). The therapeutic use of MSCs was reported in lung injury, sepsis, and necrotizing enterocolitis (NEC) caused by bacteria or viruses (Krasnodembskaya et al., 2010; Sung et al., 2016; Rodrigues et al., 2019). MSC-EVs have similar functions to their parental cells, such as antimicrobial effects, immunomodulation property, and damage tissue repairability. Compared with MSCs, MSC-EVs keep the biological function of MSCs and are more stable and less easy to tumorigenesis, making them a promising candidate for the treatment of infectious diseases (Thirabanjasak et al., 2010).

MSC-EVs had outstanding prospects in treating infectious diseases, such as respiratory infections, sepsis, and intestinal infections. The therapeutic mechanisms included direct antimicrobial effects, immunomodulation, and tissue repair. MSC-EVs exert their effect through the transfer of mRNAs, miRNAs, and proteins (Table 1). MiRNA containing EV may be a new target for the development of new therapeutic drugs. The use of MSC-EVs has several benefits, namely, (a) small vesicles, readily circulating and penetrating biological barriers, like blood–brain; (b) low tumorigenesis; and (c) stable properties, MSC-EVs may achieve a higher “dose” than MSCs due to the poor viability and considerable death of engrafted MSCs in target tissues (Barbash et al., 2003). Importantly, EVs can maintain high activities at low temperatures. All the profits make MSC-EVs a promising agent in infectious diseases.

Despite the promising progress that has been made in the treatment of MSC-EVs on infectious diseases, several challenges are faced by the field in clinical translation: (a) there is wide variability of MSC-EVs preparations in the whole process (Börger et al., 2020), such as the different productions of cell sources, purification, and identification of the final product. Careful consideration of the optimal purity and rational clinical trial design of MSC-EVs is necessary to advance large-scale clinical trials (Muraca et al., 2018). Furthermore, lacking standardized quality parameters caused discrepancies and controversies about the biology and function of MSC-EVs. Members of four societies (SOCRATES, ISCT, ISEV, and ISBT) identified potential metrics of MSC-EVs to facilitate data sharing and comparison of MSC-EVs among different studies, including biological activity, vesicle integrity, the concentration of membrane lipid vesicles, the ratio of specific lipids, the ratio of membrane lipids to protein, and the ratio of MSC to non-MSC surface antigens (Witwer et al., 2019). Each metric needs to be quantified and validated in further studies. (b) How to determine reproducible and robust parameters to predict the therapeutic potency of MSC-EVs is unsolved. The therapeutic efficacy of MSC-EVs depends not only on the cell, such as the cell source and status of MSCs, delivery dose and route (Sun et al., 2020a), and half-life and in vivo biodistribution of MSC-EVs, but also on the disease condition, such as the disease microenvironment and the time window for intervention. (c) MSC-EVs from different sources have been reported to be efficacious in various kinds of infectious diseases; the therapeutic mechanism may be different and specific for each source and disease condition. To better understand the therapeutic activity, the mode of action needs to be studied further, trying to find out the key components in MSC-EVs, target cells in injured tissues, and the involved molecular signaling cascade.

LZ: conceptualization and review. ZF: supervision. JY: writing and editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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