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.
Highlights
Extracellular vesicles (EVs) have recently gained significant attention as naturally released nanoparticles from cells—exosomes and small microvesiimportant mediators of intercellular communication, potential drug carcles[2]—are postulated to be biocomriers, and disease biomarkers
Initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off-target activity and potenconditions, able to cross biological barriers, and thought to have the potential for reduced immunogenicity as compared to other nanoparticles including synthetic liposomes or polymeric nanoparticles.[3]
Compared to synthetic drug carriers, 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)
Summary
EVs from hMSC cells have been reported in literature to show an inherent antiinflammatory activity.[22] We observed on average lower TNF alpha concentrations for EV-hydrogel-treated BMDMs this was not significant possibly due to the 24 h timepoint chosen (Figure S7b, Supporting Information) As such, these results clearly provide evidence for a biomedically functional hydrogel. We presented the very first imaging of EVs in hydrogels at the nanoscale using DDC-SEM, a powerful tool for the analysis of hydrogel morphology and spatial EV distribution and localization in 3D This simple and accessible technique may in the future assist to further characterize native EVs in biologically relevant settings such as 3D cell cultures or tissue scaffolds, and can substantially advance EV applications in biomedical research. Analysis of variance (ANOVA) followed by a post hoc test (as indicated in figure legends) was used for pairwise comparisons; differences were considered significant at p > 0.05 (Sigma Plot)
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