• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

S-RBD 修饰和 miR-486-5p 工程化间充质干细胞衍生的外泌体抑制铁死亡，减轻放射性肺损伤和长期肺纤维化。

S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells suppress ferroptosis and alleviate radiation-induced lung injury and long-term pulmonary fibrosis.

机构信息

Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China.

Laboratory of Molecular Diagnosis and Regenerative Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People's Republic of China.

出版信息

J Nanobiotechnology. 2024 Oct 26;22(1):662. doi: 10.1186/s12951-024-02830-9.

DOI:10.1186/s12951-024-02830-9
PMID:39462403
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11515248/
Abstract

BACKGROUND

Radiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem cell (MSC)-derived exosomes have regenerative effect against lung injury and the potential to intervene of RILI. However, their intervention efficacy is limited because they lack lung targeting characters and do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor and mediates interaction with host cells. MiR-486-5p is a multifunctional miRNA with angiogenic and antifibrotic potential and acts as an effector in MSC-derived exosomes. Ferroptosis is a form of cell death associated with radiation injury, its roles and mechanisms in RILI remain unclear. In this study, we developed an engineered MSC-derived exosomes with SARS-CoV-2-S-RBD- and miR-486-5p- modification and investigated their intervention effects on RIPF and action mechanisms via suppression of epithelial cell ferroptosis.

RESULTS

Adenovirus-mediated gene modification led to miR-486-5p overexpression in human umbilical cord MSC exosomes (p < 0.05), thereby constructing miR-486-5p engineered MSC exosomes (miR-486-MSC-Exo). MiR-486-MSC-Exo promoted the proliferation and migration of irradiated mouse lung epithelial (MLE-12) cells in vitro and inhibited RILI in vivo (all p < 0.05). MiR-486-MSC-Exo suppressed ferroptosis in MLE-12 cells, and an in vitro assay revealed that the expression of fibrosis-related genes is up-regulated following ferroptosis (both p < 0.05). MiR-486-MSC-Exo reversed the up-regulated expression of fibrosis-related genes induced by TGF-β1 in vitro and improved pathological fibrosis in RIPF mice in vivo (all p < 0.05). SARS-CoV-2-S-RBD-modified and miR-486-5p-engineered MSC exosomes (miR-486-RBD-MSC-Exo) were also constructed, and the distribution of DiR dye-labeled miR-486-RBD-MSC-Exo in hACE2 Sftpc-Cre mice demonstrated long-term retention in the lung (p < 0.05). MiR-486-RBD-MSC-Exo significantly improved the survival rate and pathological changes in hACE2 Sftpc-Cre RIPF mice (all p < 0.05). Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects via targeted SMAD2 inhibition and Akt phosphorylation activation (p < 0.05).

CONCLUSIONS

Engineered MSC exosomes with SARS-CoV-2-S-RBD- and miR-486-5p-modification were developed. MiR-486-RBD-MSC-Exo suppressed ferroptosis and fibrosis of MLE-12 cells in vitro, and alleviated RILI and long-term RIPF in ACE2 humanized mice in vivo. MiR-486-MSC-Exo exerted anti-fibrotic effects via SMAD2 inhibition and Akt activation. This study provides a potential approach for RIPF intervention.

摘要

背景

放射性肺损伤（RILI）与受损肺中的肺泡上皮细胞死亡和继发性纤维化有关。间充质干细胞（MSC）衍生的外泌体对肺损伤具有再生作用，并具有干预 RILI 的潜力。然而，它们的干预效果有限，因为它们缺乏肺靶向特征，并且不携带足够的特异性效应物。SARS-CoV-2 刺突糖蛋白（SARS-CoV-2-S-RBD）与血管紧张素转换酶 2（ACE2）受体结合，并介导与宿主细胞的相互作用。miR-486-5p 是一种具有血管生成和抗纤维化潜力的多功能 miRNA，作为 MSC 衍生外泌体的效应物发挥作用。铁死亡是一种与辐射损伤相关的细胞死亡形式，其在 RILI 中的作用和机制尚不清楚。在这项研究中，我们开发了一种经过工程改造的 MSC 衍生外泌体，具有 SARS-CoV-2-S-RBD 和 miR-486-5p 的修饰，并通过抑制上皮细胞铁死亡来研究其对 RIPF 的干预作用及其作用机制。

结果

腺病毒介导的基因修饰导致人脐带 MSC 外泌体中的 miR-486-5p 过表达（p<0.05），从而构建了 miR-486-5p 工程 MSC 外泌体（miR-486-MSC-Exo）。miR-486-MSC-Exo 促进了体外照射的小鼠肺上皮（MLE-12）细胞的增殖和迁移，并抑制了体内 RILI（均 p<0.05）。miR-486-MSC-Exo 抑制了 MLE-12 细胞中的铁死亡，并且体外试验表明铁死亡后纤维化相关基因的表达上调（均 p<0.05）。miR-486-MSC-Exo 逆转了体外 TGF-β1 诱导的纤维化相关基因的上调表达，并改善了体内 RIPF 小鼠的病理性纤维化（均 p<0.05）。还构建了 SARS-CoV-2-S-RBD 修饰和 miR-486-5p 工程 MSC 外泌体（miR-486-RBD-MSC-Exo）。DiR 染料标记的 miR-486-RBD-MSC-Exo 在 hACE2 Sftpc-Cre 小鼠中的分布表明其在肺中的长期保留（p<0.05）。miR-486-RBD-MSC-Exo 显著提高了 hACE2 Sftpc-Cre RIPF 小鼠的生存率和病理变化（均 p<0.05）。此外，miR-486-MSC-Exo 通过靶向 SMAD2 抑制和 Akt 磷酸化激活发挥抗纤维化作用（p<0.05）。

结论

开发了具有 SARS-CoV-2-S-RBD 和 miR-486-5p 修饰的工程 MSC 外泌体。miR-486-RBD-MSC-Exo 抑制了体外 MLE-12 细胞的铁死亡和纤维化，并减轻了 ACE2 人源化小鼠体内的 RILI 和长期 RIPF。miR-486-MSC-Exo 通过抑制 SMAD2 和激活 Akt 发挥抗纤维化作用。本研究为 RIPF 的干预提供了一种潜在的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/8222c0420192/12951_2024_2830_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/7fd4816a992d/12951_2024_2830_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/e25530c54419/12951_2024_2830_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/b5b52f7c10fe/12951_2024_2830_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/2071b47d6ee0/12951_2024_2830_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/78afcb8ec824/12951_2024_2830_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/617e106f4e0a/12951_2024_2830_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/a0136a5c4b7c/12951_2024_2830_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/8222c0420192/12951_2024_2830_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/7fd4816a992d/12951_2024_2830_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/e25530c54419/12951_2024_2830_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/b5b52f7c10fe/12951_2024_2830_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/2071b47d6ee0/12951_2024_2830_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/78afcb8ec824/12951_2024_2830_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/617e106f4e0a/12951_2024_2830_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/a0136a5c4b7c/12951_2024_2830_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20fc/11515248/8222c0420192/12951_2024_2830_Fig8_HTML.jpg

相似文献

1
S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells suppress ferroptosis and alleviate radiation-induced lung injury and long-term pulmonary fibrosis.S-RBD 修饰和 miR-486-5p 工程化间充质干细胞衍生的外泌体抑制铁死亡，减轻放射性肺损伤和长期肺纤维化。
J Nanobiotechnology. 2024 Oct 26;22(1):662. doi: 10.1186/s12951-024-02830-9.
2
Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21-5p.间充质基质细胞衍生的外泌体通过转运抗凋亡 miR-21-5p 缓解小鼠肺缺血/再灌注损伤。
Eur J Pharmacol. 2019 Jun 5;852:68-76. doi: 10.1016/j.ejphar.2019.01.022. Epub 2019 Jan 23.
3
Melatonin alleviates hyperoxia-induced lung injury through elevating MSC exosomal miR-18a-5p expression to repress PUM2 signaling.褪黑素通过提高 MSC 外泌体 miR-18a-5p 的表达来抑制 PUM2 信号从而减轻高氧诱导的肺损伤。
FASEB J. 2024 Aug 31;38(16):e70012. doi: 10.1096/fj.202400374R.
4
Mouse mesenchymal stem cell-derived exosomal miR-466f-3p reverses EMT process through inhibiting AKT/GSK3β pathway via c-MET in radiation-induced lung injury.鼠间质干细胞衍生的外泌体 miR-466f-3p 通过抑制 c-MET 逆转辐射诱导的肺损伤中的 EMT 过程通过 AKT/GSK3β 通路。
J Exp Clin Cancer Res. 2022 Apr 7;41(1):128. doi: 10.1186/s13046-022-02351-z.
5
Mesenchymal Stem Cell Derived Exosomes Suppress Neuronal Cell Ferroptosis Via lncGm36569/miR-5627-5p/FSP1 Axis in Acute Spinal Cord Injury.间质干细胞衍生的外泌体通过 lncGm36569/miR-5627-5p/FSP1 轴抑制急性脊髓损伤中的神经元细胞铁死亡。
Stem Cell Rev Rep. 2022 Mar;18(3):1127-1142. doi: 10.1007/s12015-022-10327-x. Epub 2022 Mar 7.
6
Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulate regenerative wound healing via transforming growth factor-β receptor inhibition.人脐带血间充质干细胞来源的外泌体通过抑制转化生长因子-β受体刺激再生性伤口愈合。
Stem Cell Res Ther. 2021 Aug 3;12(1):434. doi: 10.1186/s13287-021-02517-0.
7
TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis.TGF-β1 通过 miRNA 抑制 ACE2 揭示了 SARS-CoV-2 发病机制的新机制。
J Innate Immun. 2023;15(1):629-646. doi: 10.1159/000533606. Epub 2023 Aug 14.
8
Exosomes Derived from Human Adipose Mesenchymal Stem Cells Inhibits Fibrosis and Treats Oral Submucous Fibrosis via the miR-181a-5p/Smad2 Axis.脂肪间充质干细胞衍生的外泌体通过 miR-181a-5p/Smad2 轴抑制纤维化并治疗口腔黏膜下纤维化。
Tissue Eng Regen Med. 2024 Jan;21(1):123-135. doi: 10.1007/s13770-023-00579-0. Epub 2023 Sep 27.
9
Plasma exosomes from patients with acute myocardial infarction alleviate myocardial injury by inhibiting ferroptosis through miR-26b-5p/SLC7A11 axis.急性心肌梗死患者血浆外泌体通过 miR-26b-5p/SLC7A11 轴抑制铁死亡减轻心肌损伤。
Life Sci. 2023 Jun 1;322:121649. doi: 10.1016/j.lfs.2023.121649. Epub 2023 Apr 1.
10
Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence.血红素通过改善心肌细胞衰老增强间充质干细胞衍生的外泌体对梗死的心脏保护作用。
J Nanobiotechnology. 2021 Oct 21;19(1):332. doi: 10.1186/s12951-021-01077-y.

引用本文的文献

1
Mesenchymal stem cell-derived extracellular vesicles: current advances in preparation and therapeutic applications for neurological disorders.间充质干细胞衍生的细胞外囊泡：神经系统疾病制备与治疗应用的当前进展
Front Cell Dev Biol. 2025 Aug 18;13:1626996. doi: 10.3389/fcell.2025.1626996. eCollection 2025.
2
Research advances of extracellular vesicles in lung diseases.细胞外囊泡在肺部疾病中的研究进展
Cell Transplant. 2025 Jan-Dec;34:9636897251362031. doi: 10.1177/09636897251362031. Epub 2025 Aug 8.
3
Engineerable mesenchymal stem cell-derived extracellular vesicles as promising therapeutic strategies for pulmonary fibrosis.

本文引用的文献

1
The emerging roles of ferroptosis in organ fibrosis and its potential therapeutic effect.铁死亡在器官纤维化中的新兴作用及其潜在的治疗效果。
Int Immunopharmacol. 2023 Mar;116:109812. doi: 10.1016/j.intimp.2023.109812. Epub 2023 Feb 4.
2
Association between weight loss and mortality in idiopathic pulmonary fibrosis.特发性肺纤维化患者体重减轻与死亡率的相关性。
Respir Res. 2022 Dec 24;23(1):377. doi: 10.1186/s12931-022-02277-2.
3
Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model.
可工程化的间充质干细胞衍生的细胞外囊泡作为肺纤维化有前景的治疗策略。
Stem Cell Res Ther. 2025 Jul 15;16(1):367. doi: 10.1186/s13287-025-04490-4.
4
Mesenchymal stem cell-derived exosomes as a potential therapeutic strategy for ferroptosis.间充质干细胞衍生的外泌体作为铁死亡的一种潜在治疗策略。
Stem Cell Res Ther. 2025 Jul 15;16(1):368. doi: 10.1186/s13287-025-04511-2.
5
IMRC-exo alleviates limb injury by inhibiting ferroptosis in a rabbit model of deinagkistrodon acutus snakebite envenomation.在尖吻蝮蛇咬伤中毒的兔模型中，IMRC外泌体通过抑制铁死亡来减轻肢体损伤。
Sci Rep. 2025 Jul 9;15(1):24586. doi: 10.1038/s41598-025-10746-z.
6
MicroRNAs at the crossroads of exercise and ferroptosis: a regulatory bridge.运动与铁死亡交叉点上的微小RNA：一座调控桥梁
Clin Exp Med. 2025 Jul 6;25(1):234. doi: 10.1007/s10238-025-01766-0.
7
Ginsenoside Rh2-Pretreated Mesenchymal Stem Cell Exosomes Ameliorate Collagen-Induced Arthritis via N6-Methyladenosine Methylation.人参皂苷Rh2预处理的间充质干细胞外泌体通过N6-甲基腺苷甲基化改善胶原诱导的关节炎。
Biomater Res. 2025 Jun 11;29:0220. doi: 10.34133/bmr.0220. eCollection 2025.
8
Human umbilical cord mesenchymal stem cell-derived exosomes mitigate acute radiation-induced intestinal oxidative damage via the Nrf2/HO-1/NQO1 signaling pathway.人脐带间充质干细胞来源的外泌体通过Nrf2/HO-1/NQO1信号通路减轻急性辐射诱导的肠道氧化损伤。
PLoS One. 2025 Jun 6;20(6):e0324238. doi: 10.1371/journal.pone.0324238. eCollection 2025.
9
From Mechanism to Therapy: The Role of MSC-EVs in Alleviating Radiation-Induced Injuries.从机制到治疗：间充质干细胞外泌体在减轻辐射诱导损伤中的作用
Pharmaceutics. 2025 May 16;17(5):652. doi: 10.3390/pharmaceutics17050652.
10
Therapeutic Potential of Umbilical Cord MSC-Derived Exosomes in a Severe Dry Eye Rat Model: Enhancing Corneal Protection and Modulating Inflammation.脐带间充质干细胞衍生外泌体在严重干眼大鼠模型中的治疗潜力：增强角膜保护和调节炎症
Biomedicines. 2025 May 11;13(5):1174. doi: 10.3390/biomedicines13051174.
在博来霉素模型中，铁死亡抑制和铁蓄积减轻可缓解肺纤维化。
Redox Biol. 2022 Nov;57:102509. doi: 10.1016/j.redox.2022.102509. Epub 2022 Oct 18.
4
Microrna-486-5P Regulates Human Pulmonary Artery Smooth Muscle Cell Migration via Endothelin-1.微小 RNA-486-5P 通过内皮素-1 调节人肺动脉平滑肌细胞迁移。
Int J Mol Sci. 2022 Sep 8;23(18):10400. doi: 10.3390/ijms231810400.
5
Inhalable dry powder mRNA vaccines based on extracellular vesicles.基于细胞外囊泡的可吸入干粉mRNA疫苗。
Matter. 2022 Sep 7;5(9):2960-2974. doi: 10.1016/j.matt.2022.06.012. Epub 2022 Jul 11.
6
Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine.用带有重组 SARS-CoV-2 受体结合域的外泌体作为可吸入的 COVID-19 疫苗。
Nat Biomed Eng. 2022 Jul;6(7):791-805. doi: 10.1038/s41551-022-00902-5. Epub 2022 Jul 4.
7
Therapeutic Strategy of Mesenchymal-Stem-Cell-Derived Extracellular Vesicles as Regenerative Medicine.间充质干细胞衍生细胞外囊泡的治疗策略作为再生医学。
Int J Mol Sci. 2022 Jun 9;23(12):6480. doi: 10.3390/ijms23126480.
8
miRNA-486-5p: signaling targets and role in non-malignant disease.miRNA-486-5p：信号靶标及其在非恶性疾病中的作用。
Cell Mol Life Sci. 2022 Jun 22;79(7):376. doi: 10.1007/s00018-022-04406-y.
9
Novel drug delivery systems and disease models for pulmonary fibrosis.新型药物输送系统和肺纤维化疾病模型。
J Control Release. 2022 Aug;348:95-114. doi: 10.1016/j.jconrel.2022.05.039. Epub 2022 Jun 3.
10
Transcriptional inhibition of miR-486-3p by BCL6 upregulates Snail and induces epithelial-mesenchymal transition during radiation-induced pulmonary fibrosis.BCL6 通过转录抑制 miR-486-3p 上调 Snail，诱导放射性肺纤维化中的上皮间质转化。
Respir Res. 2022 Apr 28;23(1):104. doi: 10.1186/s12931-022-02024-7.