Targeted mRNA Nanoparticles Ameliorate Blood-Brain Barrier Disruption Postischemic Stroke by Modulating Microglia Polarization
Document Type
Article
Publication Date
1-30-2024
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.
Identifier
85183527306 (Scopus)
Publication Title
ACS Nano
External Full Text Location
https://doi.org/10.1021/acsnano.3c09817
e-ISSN
1936086X
ISSN
19360851
PubMed ID
38227975
First Page
3260
Last Page
3275
Issue
4
Volume
18
Grant
NCTIB2022HS02002
Fund Ref
Natural Science Foundation of Shanghai Municipality
Recommended Citation
Gao, Mingzhu; Li, Yan; Ho, William; Chen, Chen; Chen, Qijing; Li, Fengshi; Tang, Maoping; Fan, Qiuyue; Wan, Jieqing; Yu, Weifeng; Xu, Xiaoyang; Li, Peiying; and Zhang, Xue Qing, "Targeted mRNA Nanoparticles Ameliorate Blood-Brain Barrier Disruption Postischemic Stroke by Modulating Microglia Polarization" (2024). Faculty Publications. 679.
https://digitalcommons.njit.edu/fac_pubs/679
