Engineered Extracellular Vesicles Loaded with MiR-100-5p Antagonist Selectively Target the Lesioned Region to Promote Recovery from Brain Damage
Yahong Cheng1 · Chengcheng Gai1 · Yijing Zhao1 · Tingting Li1 · Yan Song1 · Qian Luo2 · Danqing Xin1 · Zige Jiang1 · Wenqiang Chen3 · Dexiang Liu2 · Zhen Wang11 Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
2 Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
3 Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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.
Keywords
MicroRNAs; Extracellular vesicles; Protein phosphatase 3 catalytic subunit alpha; Neuronal survival; Neonatal hypoxic-ischemic brain damage
