Utilizing Extracellular Vesicles for Eliminating 'Unwanted Molecules': Harnessing Nature's Structures in Modern Therapeutic Strategies

Abstract

Extracellular vesicles (EVs) are small phospholipid bilayer-bond structures released by diverse cell types into the extracellular environment, maintaining homeostasis of the cell by balancing cellular stress. This article provides a comprehensive overview of extracellular vesicles, their heterogeneity, and diversified roles in cellular processes, emphasizing their importance in the elimination of unwanted molecules. They play a role in regulating oxidative stress, particularly by discarding oxidized toxic molecules. Furthermore, endoplasmic reticulum stress induces the release of EVs, contributing to distinct results, including autophagy or ER stress transmission to following cells. ER stress-induced autophagy is a part of unfolded protein response (UPR) and protects cells from ER stress-related apoptosis. Mitochondrial-derived vesicles (MDVs) also play a role in maintaining homeostasis, as they carry damaged mitochondrial components, thereby preventing inflammation. Moreover, EVs partake in regulating aging-related processes, and therefore they can potentially play a crucial role in anti-aging therapies, including the treatment of age-related diseases such as Alzheimer's disease or cardiovascular conditions. Overall, the purpose of this article is to provide a better understanding of EVs as significant mediators in both physiological and pathological processes, and to shed light on their potential for therapeutic interventions targeting EV-mediated pathways in various pathological conditions, with an emphasis on age-related diseases.

Keywords: age-related diseases; aging process; autophagy; endoplasmic reticulum stress; extracellular vesicles; mitochondrial-derived vesicles; oxidative stress.

Figure 1

Schematic visualization of extracellular vesicles division based on their size and mode of release. Exosomes are released due to MVBs’ fusion with the plasma membrane, microvesicles are formed by the direct outward budding of the membrane, and the formation of apoptotic bodies occurs during apoptosis [4].

Figure 2

Schematic visualization of direct and indirect ways of oxidative stress regulation executed by EVs. To reduce oxidative stress, EVs can directly deliver antioxidant compounds such as CAT, SOD, and GST, or indirectly transport single or multiple regulators to target cells. Conversely, for the aggravation of oxidative stress, EVs can deliver oxides such as ROS and RNS directly to recipient cells, while oxide-producing agents or multiple regulators can be delivered indirectly [25].

Figure 3

The diagram illustrates various mechanisms of DOX-induced EVs release. These mechanisms include the activation of TSAP6 by p53, lipid peroxidation, and an increase of cytosolic calcium level resulting from the repression of the electron transport chain [33,53,54,55,56].

Figure 4

Schematic visualization of ER stress possible results, which in the end leads either to adaptation for survival or induction of apoptosis, as well as the proteins that are directly involved in the UPR signaling pathway, which are BIP, ATF6, PERK, and IRE1α [59,62,64,65].

Figure 5

Schematic visualization of interactions between EVs’ release and ER stress occurrence, as well as transmission. If the cell X releases EVs that are internalized by cell Y (Direction A), there is a possibility that the content of EVs might cause ER stress in the cell Y. Under stress, cell Y releases EVs internalized by cell X (Direction B), which might transmit ER stress to cell X or cause another effect [70,73,74].

Figure 6

Schematic visualization of different autophagy pathways and their association with exosome release. During macroautophagy, entire regions of the cytosol are enclosed within autophagosomes, which subsequently fuse with MVBs or lysosomes, resulting in the degradation of their contents. In contrast, microautophagy involves the internalization of small cytoplasmic components through the inward invagination of the lysosomal membrane. CMA involves the degradation of unfolded proteins, and is mediated by the binding of hsc70 to the lysosomal membrane. Autophagy regulates exosome secretion through autophagy-related proteins located on the membrane of MVBs. In this process, the ESCRT machinery and hsc70 are involved, facilitating the incorporation of proteins into ILVs [91,95].

Figure 7

The diagram picturing two alternative pathways of sorting damaged mitochondrial components into mitochondrial-derived vesicles. Either is the MDVs formation initiated by SNX9 that recognizes and binds to the mitochondrial membrane, or the fragments intended for degradation are decomposed in lysosomes, which is regulated by PRKN [102,103,104].