Targeted mRNA Nanoparticles Ameliorate Blood-Brain Barrier Disruption Postischemic Stroke by Modulating Microglia Polarization

Mingzhu Gao, Yan Li, William Ho, Chen Chen, Qijing Chen, Fengshi Li, Maoping Tang, Qiuyue Fan, Jieqing Wan, Weifeng Yu, Xiaoyang Xu, Peiying Li, Xue Qing Zhang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The ischemic stroke is a major global health concern, with high mortality and disability rates. Unfortunately, there is a dearth of effective clinical interventions for managing poststroke neuroinflammation and blood-brain barrier (BBB) disruption that are crucial for the brain injury evolving and neurological deficits. By leveraging the pathological progression of an ischemic stroke, we developed an M2 microglia-targeting lipid nanoparticle (termed MLNP) approach that can selectively deliver mRNA encoding phenotype-switching interleukin-10 (mIL-10) to the ischemic brain, creating a beneficial feedback loop that drives microglial polarization toward the protective M2 phenotypes and augments the homing of mIL-10-loaded MLNPs (mIL-10@MLNPs) to ischemic regions. In a transient middle cerebral artery occlusion (MCAO) mouse model of an ischemic stroke, our findings demonstrate that intravenously injected mIL-10@MLNPs induce IL-10 production and enhance the M2 polarization of microglia. The resulting positive loop reinforces the resolution of neuroinflammation, restores the impaired BBB, and prevents neuronal apoptosis after stroke. Using a permanent distal MCAO mouse model of an ischemic stroke, the neuroprotective effects of mIL-10@MLNPs have been further validated by the attenuation of the sensorimotor and cognitive neurological deficits. Furthermore, the developed mRNA-based targeted therapy has great potential to extend the therapeutic time window at least up to 72 h poststroke. This study depicts a simple and versatile LNP platform for selective delivery of mRNA therapeutics to cerebral lesions, showcasing a promising approach for addressing an ischemic stroke and associated brain conditions.

Original languageEnglish (US)
Pages (from-to)3260-3275
Number of pages16
JournalACS Nano
Volume18
Issue number4
DOIs
StatePublished - Jan 30 2024

All Science Journal Classification (ASJC) codes

  • General Materials Science
  • General Engineering
  • General Physics and Astronomy

Keywords

  • ischemic stroke
  • lipid nanoparticle
  • mRNA
  • phenotypic switch
  • targeted delivery

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