山东大学王震课题组的一项最新研究开发出负载MiR-100-5p拮抗剂的工程细胞外囊泡选择性靶向损伤区域以促进脑损伤的恢复。该项研究成果发表在2025年4月1日出版的《神经科学通报》上。

研究团队证明了新生小鼠HI损伤后损伤皮质中的miR-100-5p水平升高。在脑中敲低miR-100-5p的表达，通过抑制HI损伤后的裂解caspase-3水平、小胶质细胞激活和促炎症细胞因子的释放，减轻脑损伤并促进功能恢复。含有神经元靶向狂犬病病毒糖蛋白（RVG）和miR-100-5p拮抗剂（RVG- ev - antagomir）的工程化细胞外囊泡（ev）选择性靶向脑病变，并在鼻内递送后降低miR-100-5p水平。注射前和注射后均显示出治疗效果。

在机制上，研究团队发现蛋白磷酸酶3催化亚基α (Ppp3ca)是miR-100-5p的一个新的候选靶基因，抑制HI损伤后c-Fos的表达和神经元凋亡。总之，他们的无创方法主题化工程ev将miR-100-5p拮抗剂递送到大脑，通过靶向Ppp3ca抑制神经元凋亡，显著改善HI损伤后的功能恢复。

据悉，缺氧缺血性脑损伤具有很高的死亡或终身残疾风险，但有效的治疗方法仍然缺乏。

附：英文原文

Title: Engineered Extracellular Vesicles Loaded with MiR-100-5p Antagonist Selectively Target the Lesioned Region to Promote Recovery from Brain Damage

Author: Cheng, Yahong, Gai, Chengcheng, Zhao, Yijing, Li, Tingting, Song, Yan, Luo, Qian, Xin, Danqing, Jiang, Zige, Chen, Wenqiang, Liu, Dexiang, Wang, Zhen

Issue&Volume: 2025-04-01

Abstract: Hypoxic-ischemic (HI) brain damage poses a high risk of death or lifelong disability, yet effective treatments remain elusive. Here, we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice. Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery, through inhibiting the cleaved-caspase-3 level, microglia activation, and the release of proinflammation cytokines following HI injury. Engineered extracellular vesicles (EVs) containing neuron-targeting rabies virus glycoprotein (RVG) and miR-100-5p antagonists (RVG-EVs-Antagomir) selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery. Both pre- and post-HI administration showed therapeutic benefits. Mechanistically, we identified protein phosphatase 3 catalytic subunit alpha (Ppp3ca) as a novel candidate target gene of miR-100-5p, inhibiting c-Fos expression and neuronal apoptosis following HI insult. In conclusion, our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.

DOI: 10.1007/s12264-025-01376-6

Source: https://link.springer.com/article/10.1007/s12264-025-01376-6