<br>靶向 mRNA 纳米颗粒通过调节小胶质细胞极化改善缺血后中风的血脑屏障破坏,ACS Nano

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靶向 mRNA 纳米颗粒通过调节小胶质细胞极化改善缺血后中风的血脑屏障破坏
ACS Nano ( IF 15.8 ) Pub Date : 2024-01-16 , DOI: 10.1021/acsnano.3c09817
Mingzhu Gao _{1,

2} , Yan Li _{3,

4} , William Ho ₅ , Chen Chen _{3,

4} , Qijing Chen _{1,

2} , Fengshi Li _{4,

6} , Maoping Tang _{1,

2} , Qiuyue Fan _{3,

4} , Jieqing Wan _{4,

6} , Weifeng Yu _{3,

4} , Xiaoyang Xu _{5,

7} , Peiying Li _{3,

4,

8} , Xue-Qing Zhang _{1,

2}

Affiliation

缺血性中风是全球主要的健康问题，死亡率和致残率很高。不幸的是，缺乏有效的临床干预措施来管理中风后神经炎症和血脑屏障（BBB）破坏，而这些对脑损伤的发展和神经功能缺损至关重要。通过利用缺血性中风的病理进展，我们开发了一种靶向 M2 小胶质细胞的脂质纳米颗粒（称为 MLNP）方法，该方法可以选择性地将编码表型转换白细胞介素 10 (m IL-10 ) 的 mRNA 递送至缺血性大脑，从而创造有益的治疗效果。反馈回路，驱动小胶质细胞极化向保护性 M2 表型，并增强 m IL-10负载 MLNP (m IL-10 @MLNP) 归巢至缺血区域。在缺血性中风的短暂性大脑中动脉闭塞 (MCAO) 小鼠模型中，我们的研究结果表明，静脉注射 m IL-10 @MLNP 可诱导 IL-10 产生并增强小胶质细胞的 M2 极化。由此产生的正环路可增强神经炎症的消退，恢复受损的血脑屏障，并防止中风后神经元凋亡。使用缺血性中风的永久性远端 MCAO 小鼠模型，通过减弱感觉运动和认知神经缺陷，进一步验证了 m IL-10 @MLNP 的神经保护作用。此外，所开发的基于 mRNA 的靶向治疗具有将治疗时间窗口延长至少至中风后 72 小时的巨大潜力。这项研究描述了一个简单且多功能的 LNP 平台，用于选择性地将 mRNA 疗法递送至脑损伤，展示了一种解决缺血性中风和相关脑部疾病的有前景的方法。

"点击查看英文标题和摘要"

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

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.

更新日期：2024-01-16

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