Investigating the Therapeutic Efficacy of Quality-Controlled, miR-146a-5p-Enriched Small Extracellular Vesicles Derived From MSCs Against Idiopathic Pulmonary Fibrosis

Abstract

Small extracellular vesicles derived from umbilical cord mesenchymal stem cells (UC-sEvs) may be used for the treatment of idiopathic pulmonary fibrosis (IPF) because of their ability to control inflammation and inhibit fibrosis. However, the lack of clarity regarding the treatment mechanism of IPF and the corresponding quality standards limit the clinical application of these small extracellular vesicles. Here, we established a good manufacturing practice (GMP) grade process for isolating UC-sEvs, and RNA-seq was performed to screen for potential therapeutic cargo in the product to confirm the therapeutic effect of nebulized UC-sEv agents against IPF. Functionally, UC-sEvs inhibited the pulmonary inflammatory response by regulating macrophage function, thereby suppressing the bleomycin toxicity-induced progression of fibrosis. Mechanistically, miR-146a-5p enrichment in UC-sEvs may be involved in alleviating bleomycin-induced IPF by targeting TRAF6/IRAK1 to negatively regulate inflammation. The proposed quality control strategy ensures the stability of the product across three batches, with RNA-seq analysis revealing highly similar miRNA expression profiles. The feasibility of using miR-146a-5p as a key therapeutic molecule has been validated. Finally, on the basis of the results of pharmacodynamics and key therapeutic molecule studies, we provided a detailed quality control standard for IPF therapy by nebulizing UC-sEv. These findings help understand how sEvs impact IPF and the possible consequences of their therapeutic usage and offer a quality standard reference. Graphical Abstract

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