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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