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Abstract
GPCRs activate atypical p38 signaling to drive vascular inflammation. Recent studies have highlighted atypical p38 signaling as an attractive therapeutic target for a range of pathological signaling. However, current approaches to block atypical p38 signaling are limited to a single cell-penetrating peptide inhibitor (PT5). Our hypothesis is that we can generate a stable cell line to produce extracellular vesicles (EVs) preloaded with monomeric Red fluorescent Protein conjugated PT5 (mRFP-PT5) as an alternative approach for inhibitor delivery to cells. We successfully generated an endothelial cell line that produces mRFP labeled PT5 packaged into EVs. We were able to isolate PT5 loaded EVs, which could block p38 atypical signaling not only in EV producing cells, but in recipient endothelial cells as well. These data provide evidence that EVs are suitable vehicles for delivering engineered biomolecules intracellularly to block atypical p38 signaling.