Engineering Extracellular Vesicles with the Tools of Enzyme Prodrug Therapy

Abstract

Extracellular vesicles (EVs) have recently gained significant attention as important mediators of intercellular communication, potential drug carriers, and disease biomarkers. These natural cell-derived nanoparticles are postulated to be biocompatible, stable under physiological conditions, and to show reduced immunogenicity as compared to other synthetic nanoparticles. Although initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off-target activity and potential “dilution effects” upon systemic administration which may affect their ability to reach their target tissues. To fully exploit their therapeutic potential, EVs are embedded into implantable biomaterials designed to achieve local delivery of therapeutics taking advantage of enzyme prodrug therapy (EPT). In this first application of EVs for an EPT approach, EVs are used as smart carriers for stabilizing enzymes in a hydrogel for local controlled conversion of benign prodrugs to active antiinflammatory compounds. It is shown that the natural EVs’ antiinflammatory potential is comparable or superior to synthetic carriers, in particular upon repeated long-term incubations and in different macrophage models of inflammation. Moreover, density-dependent color scanning electron microscopy imaging of EVs in a hydrogel is presented herein, an impactful tool for further understanding EVs in biological settings.

Mastering the Tools: Natural versus Artificial Vesicles in Nanomedicine

“…In 2018, Fuhrmann et al used EVs as carriers for the stabilization of selected enzymatic cargoes within a hydrogel for a controlled release and conversion of a benign prodrug, to be transformed locally, into an antiinflammatory drug. [186] The authors loaded the hMSC-derived EVs with -glucuronidase and encapsulated them within a poly-(vinyl alcohol) (PVA) hydrogel, followed by stabilization with PEG, in order to generate biocompatible hydrogels with a diameter of 8 mm and thickness of 2 mm. In this way, they achieved a local and sustained conversion of the curcumin -dglucuronide precursor into free curcumin, with a local and acute anti-inflammatory effect.…”

“…The authors demonstrated that EV hydrogels may have an anti-inflammatory potential greater than liposome-based hydrogels, even in the absence of the substrate. [186] In Table 1 are listed the hydrogel based approaches for EV delivery and application, with the details about EV source, hydrogel composition, the physiopathological context, and the specific results.…”

Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery

“…In other words EVs were used as smart carriers to stabilize the enzymes in a hydrogel where local controlled conversion of a prodrug to the active compound would take place. In the specific case an anti-inflammatory product was studied and EVs were demonstrated to confer comparable or superior antiinflammatory activity to that of synthetic carriers [179].…”

Biotransporting Biocatalytic Reactors toward Therapeutic Nanofactories

“…Hydrogels are a superior platform for embedding not only synthetic vesicles (liposomes) but also naturally occurring vesicles, i.e., extracellular vesicles (EVs) or exosomes. Stevens and co‐workers recently reported that EVs with encapsulated β‐glucuronidase were successfully embedded in a PVA‐based hydrogel without sacrificing the enzymatic activity and showed that the EV–hydrogel hybrid produced anti‐inflammatory drugs (curcumin) upon addition of curcumin‐β‐ d ‐glucuronide . Exosomes are involved in numerous physiological functions, therefore this exosome‐localizing technique is a promising approach for exosome‐based therapeutics.…”