The administration of (stem) cell-derived extracellular vesicles (EVs) promotes tissue repair through management of different inflammatory, proliferative and remodeling processes in the body. Despite the widely observed biological and therapeutic roles of EVs in wound healing and tissue repair, knowledge on how EVs activate recipient cells and which EV cargo is responsible for the subsequent functional effects is limited. Recent studies hint toward an important role for proteins as functional EV cargo. Here, we provide an overview of how EV-associated proteins promote tissue repair processes and discuss current challenges in evaluating their contribution to EV function and future directions for translating fundamental insights into clinically relevant EV therapies. Extracellular Vesicles: Natural Vehicles of Biological Cargo in Tissue Homeostasis and RepairApart from conventional secretory pathways (see Glossary), cells secrete proteins, nucleic acids, and lipids that are delivered to other cells through vesicles generated via the endosomal pathway or upon direct budding of the plasma membrane. Collectively, these vesicles are called extracellular vesicles (EVs). Despite initial thoughts about being nothing more than the garbage disposal system of cells, it is now well established that these EVs also play important roles in tissue homeostasis through short-and long-distance intercellular communication. EVs isolated from multiple cell types, tissues, and body fluids promote endogenous tissue repair through the modulation of several physiological processes in the body. As a result, EVs bear potential as therapeutics in regenerative medicine, and have been demonstrated to be a functional component of the stem and progenitor cell secretome [1]. Indeed, EVs have been found to promote different reparative processes in the body. Although many studies have set out to identify the functional cargo and cell activation pathways of EVs in tissue repair, the exact mechanisms by which these EVs exert their effects remain elusive. In this review, we describe why proteins expressed on (or in) EVs might be important contributors to EV function, and address the role of specific EV proteins in tissue repair processes in the body. Challenges in the study of individual EV-associated proteins and the implication for the translation of these insights into EV therapeutics will be discussed. EV Biogenesis and Recipient Cell ActivationEVs may be classified based on a set of characteristics including their size, density, process of cellular release, and their protein/lipid composition [2,3]. Three such subgroups are exosomes, microvesicles, and apoptotic bodies (Box 1). Although distinct in biogenesis, it is hard to capture and assign the heterogeneous population of EVs upon isolation toward different classes as they share overlapping physiochemical characteristics and biological markers [4]. To encompass all different vesicle types, the general term EV is increasingly used, as also in this review. EVs are enriched in distinct proteins and...

Extracellular vesicles (EVs) are small vesicles secreted by cells and have gained increasing interest as both drug delivery vehicles or as cell‐free therapeutics for regenerative medicine. To achieve optimal therapeutic effects, strategies are being developed to prolong EV exposure to target organs. One promising approach to achieve this is through EV‐loaded injectable hydrogels. In this study, the use of a hydrogel based on ureido‐pyrimidinone (UPy) units coupled to poly(ethylene glycol) chains (UPy‐hydrogel) is examined as potential delivery platform for EVs. The UPy‐hydrogel undergoes a solution‐to‐gel transition upon switching from a high to neutral pH, allowing immediate gelation upon administration into physiological systems. Here, sustained EV release from the UPy‐hydrogel measured over a period of 4 d is shown. Importantly, EVs retain their functional capacity after release. Upon local administration of fluorescently labeled EVs incorporated in a UPy‐hydrogel in vivo, EVs are still detected in the UPy‐hydrogel after 3 d, whereas in the absence of a hydrogel, EVs are internalized by fat and skin tissue near the injection site. Together, these data demonstrate that UPy‐hydrogels provide sustained EV release over time and enhance local EV retention in vivo, which could contribute to improved therapeutic efficacy upon local delivery and translation toward new applications.

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