Biomodified Extracellular Vesicles Remodel the Intestinal Microenvironment to Overcome Radiation Enteritis

Abstract

Ionizing radiation (IR) is associated with the occurrence of enteritis, and protecting the whole intestine from radiation-induced gut injury remains an unmet clinical need. Circulating extracellular vesicles (EVs) are proven to be vital factors in the establishment of tissue and cell microenvironments. In this study, we aimed to investigate a radioprotective strategy mediated by small EVs (exosomes) in the context of irradiation-induced intestinal injury. We found that exosomes derived from donor mice exposed to total body irradiation (TBI) could protect recipient mice against TBI-induced lethality and alleviate radiation-induced gastrointestinal (GI) tract toxicity. To enhance the protective effect of EVs, profilings of mouse and human exosomal microRNAs (miRNAs) were performed to identify the functional molecule in exosomes. We found that miRNA-142-5p was highly expressed in exosomes from both donor mice exposed to TBI and patients after radiotherapy (RT). Moreover, miR-142 protected intestinal epithelial cells from irradiation-induced apoptosis and death and mediated EV protection against radiation enteritis by ameliorating the intestinal microenvironment. Then, biomodification of EVs was accomplished via enhancing miR-142 expression and intestinal specificity of exosomes, and thus improved EV-mediated protection from radiation enteritis. Our findings provide an effective approach for protecting against GI syndrome in people exposed to irradiation.

MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice

“…We then investigated whether delivering miR-200 via LNPs could alleviate the phenotypic changes within the intestinal epithelium of Dgcr8 -deficient mice following damage induced by irradiation in a dose-dependent manner . LNPs-miR-200 reduced the extent of injury in the epithelium and rescued Dgcr8 KO mice from death, evidenced by increased overall survival and a decrease in the number of damaged crypts in a dose-dependent manner (Figure E–G).…”