Exosome-based therapies for mucosal delivery

Abstract

Exosomes are membrane-bound extracellular nanovesicles secreted by most cells and found in multiple sources, including bodily fluids, plants, fruit, and bovine milk. They play an important role as mediators of intercellular communication, having a distinct ability to carry small molecules, proteins, and nucleic acids to recipient cells over large distances. Moreover, competency in crossing usually poorly permeable biological barriers has led to their promising use in diagnostics and in therapeutics, either as therapeutic entities on their own or as drug delivery vehicles, with superior stability, biocompatibility, circulation time and target specificity in comparison to conventional drug delivery systems. The aim of this review is to summarise and critically discuss the current literature on the use of exosomes in a therapeutic setting, with a particular focus on their use as drug delivery vehicles for mucosal drug delivery.

Introduction

Exosomes are membrane-bound extracellular vesicles with a diameter ranging from 30 nm to 150 nm, secreted by the endosomal pathway into extracellular space post biogenesis (Rahmati et al., 2020). These structures consist of a lipid bilayer embedded with specific membrane proteins, along with other components such as RNA, DNA and cytosolic proteins (Zaborowski et al., 2015). The composition in protein, lipids and cargo varies depending on the ancestry of the exosomes as they retain certain components and characteristics of the parent cell (Lu and Huang, 2020, Bhatti et al., 2019). Exosomes are secreted by most mammalian cells and are present in most biological fluids, including blood, urine, amniotic fluid, saliva, cerebrospinal fluid, and breast milk (Zhang et al., 2019). The cellular origin directly influences the biological function of exosomes (He et al., 2018). By facilitating protein expression through transfer of functional genetic material via receptor-ligand interactions, direct fusion of membranes, or internalization via endocytosis, exosomes can induce modifications in the phenotype of the target cells (Zhang et al., 2019, Ha et al., 2016, Batrakova and Kim, 2015).

Exosomes have been known to modulate cell development, homeostasis and cell proliferation (Ha et al., 2016, Pegtel and Gould, 2019). For example, mesenchymal stem cell-derived exosomes (MSC-Exo) have the capacity to induce tissue regeneration by transferring cytokines, growth factors, miRNA, mRNA and other functional cargo to recipient cells (de Toro et al., 2015). In addition, exosomes have the capacity to regulate the immune response and promote the progression of diseases, such as cancer, neurodegenerative, cardiovascular, infectious, and metabolic diseases (de Toro et al., 2015, Bebelman et al., 2018, Ghidoni et al., 2008).

Exosomes exhibit a natural propensity to double as a therapeutic platform and as a diagnostic tool (biomarkers) for numerous diseases. Recently, exosomes have been investigated for their potential to act as drug delivery vehicles due to their high in vivo stability and ability to cross multiple biological barriers (Salunkhe et al., 2020, Liang et al., 2021). While strides have been made in utilizing exosomes as prognostic markers, or as drug delivery vehicles for cancer therapeutics, the extent of research on the use of exosomes outside of the realm of cancer has not been as widespread. The aim of this review is to discuss the current literature on the use of exosomes in mucosal drug delivery. We further touch on the stability of exosomes at various mucosal surfaces and drug loading of exosomes as key challenges in their use as drug carriers for mucosal delivery. Furthermore, the mechanisms by which exosomes traverse different mucosal barriers are also highlighted. Finally, we also comment on current challenges in translating exosome research into the clinical setting and provide directions for future studies.