Engineered Extracellular Vesicles Loaded with MiR-100-5p Antagonist Selectively Target the Lesioned Region to Promote Recovery from Brain Damage
Open accessAbstract
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.
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- Authors
- Cheng, Y., Gai, C., Zhao, Y., Li, T., Song, Y., Luo, Q., Xin, D., Jiang, Z., Chen, W., Liu, D., & Wang, Z.
- Affiliations
- Shandong University (CN)
- Corresponding author
- Liu, Dexiang
- Wang, Zhen
- Venue
- Neuroscience Bulletin
- Published
- 2025-04-01
- Volume
- 41
- Issue
- 6
- Pages
- 1021-1040
- ISSN
- 1995-8218 (ISSN-L)
- 1673-7067
- PMC
- PMC12158875
- OpenAlex
- W4409087275
- Semantic Scholar
- e42285359a358fee1cbbbb3de13d3ae94f8231c6
- Cited by
- 5
- References
- 52
- Citations by year
- 2026: 3 · 2025: 2
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-11-05)
- Open access
- hybrid
- doi.org
- Locations
- Neuroscience Bulletin (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- engineered extracellular vesicles, hypoxic-ischemic brain injury, intranasal drug delivery, PPP3CA, c-fos, neuronal apoptosis, microglial activation, neuroinflammation, functional recovery, neonatal brain injury
- MeSH terms
- Extracellular Vesicles, Antagomirs, Animals, Animals, Newborn, Brain Injuries, Glycoproteins, Male, Mice, Inbred C57BL, Peptide Fragments, Viral Proteins, Apoptosis, Recovery of Function, Hypoxia-Ischemia, Brain, MicroRNAs, Mice
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