Biomodified Extracellular Vesicles Remodel the Intestinal Microenvironment to Overcome Radiation Enteritis

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.

电离辐射（Ionizing Radiation, IR）与肠炎的发生存在显著关联，而实现全肠道防护以抵御辐射诱导的肠损伤，仍是尚未满足的临床需求。循环细胞外囊泡（extracellular vesicles, EVs）已被证实是构建组织与细胞微环境的关键调控因子。本研究旨在探究小细胞外囊泡（外泌体，small EVs, exosomes）介导的辐射防护策略，以应对辐射诱导的肠损伤问题。研究发现，经全身照射（total body irradiation, TBI）的供体小鼠来源的外泌体，可保护受体小鼠抵御TBI诱导的致死效应，并缓解辐射引发的胃肠道（gastrointestinal tract, GI）毒性。为增强细胞外囊泡的防护效果，本研究对小鼠及人源外泌体的微小RNA（microRNAs, miRNAs）表达谱进行分析，以鉴定外泌体中的功能性分子。结果显示，miR-142-5p在经TBI处理的供体小鼠外泌体，以及接受放疗（radiotherapy, RT）的患者外泌体中均呈高表达。此外，miR-142可保护肠上皮细胞免受辐射诱导的凋亡与死亡，并通过改善肠道微环境，介导细胞外囊泡对辐射性肠炎的防护作用。随后，本研究通过上调miR-142的表达水平，并赋予外泌体肠道靶向特异性，完成了细胞外囊泡的生物修饰，进而提升了细胞外囊泡介导的辐射性肠炎防护效果。本研究结果为受辐射暴露人群的胃肠道综合征防护提供了一种有效策略。