ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation.
ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation.
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DOI：
10.1016/j.bioactmat.2022.03.040
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发表时间：
2023-01
影响因子：
18.9
通讯作者：
Mao Z
中科院分区：
文献类型：
--
作者：
Jin L;Zhu Z;Hong L;Qian Z;Wang F;Mao Z
缺血性脑卒中是一种急性、严重的脑血管疾病，严重影响人们的身体健康，给社会带来巨大的经济负担。小胶质细胞作为中枢神经系统（CNS）重要的天然免疫成分，在神经损伤的战斗中是一把双刃剑，具有促炎M1和抗炎M2两种表型。高迁移率族蛋白1（HMGB 1）是一种有效的促炎介质，可促进小胶质细胞的M1极化。18β-甘草次酸（GA）是一种有效的HMGB 1细胞内抑制剂，但水溶性差，毒性呈剂量依赖性。为了克服GA递送的缺点并提高脑缺血治疗的功效，本文中，我们设计了活性氧（ROS）响应性聚合物-药物缀合物纳米颗粒（DGA）以通过抑制核HMGB 1的易位来操纵小胶质细胞极化。DGA对脑卒中小鼠具有良好的治疗效果，如减少梗死体积，恢复运动功能，抑制M1小胶质细胞活化和增强M2活化，以及诱导神经发生。总之，我们的工作证明了HMGB 1和小胶质细胞极化之间的密切联系，为应对炎症性小胶质细胞相关疾病提出了潜在的策略。我们合成了GA-硼酸酯-缀合的二乙氨基乙烯-葡聚糖聚合物-药物缀合物纳米粒。DGA纳米颗粒实现ROS响应性药物释放。DGA纳米颗粒抑制核HMGB 1的细胞质易位，从而将小胶质细胞调节为M2表型。DGA纳米颗粒有效地减轻中风的病理，减少梗死体积，并增强神经发生。
Ischemic stroke is an acute and serious cerebral vascular disease, which greatly affects people's health and brings huge economic burden to society. Microglia, as important innate immune components in central nervous system (CNS), are double-edged swords in the battle of nerve injury, considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes. High mobility group box 1 (HMGB1) is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia. 18β-glycyrrhetinic acid (GA) is an effective intracellular inhibitor of HMGB1, but of poor water solubility and dose-dependent toxicity. To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy, herein, we designed reactive oxygen species (ROS) responsive polymer-drug conjugate nanoparticles (DGA) to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1. DGA presented excellent therapeutic efficacy in stroke mice, as evidenced by the reduction of infarct volume, recovery of motor function, suppressed of M1 microglia activation and enhanced M2 activation, and induction of neurogenesis. Altogether, our work demonstrates a close association between HMGB1 and microglia polarization, suggesting potential strategies for coping with inflammatory microglia-related diseases. We synthesized GA-boronate ester-conjugated diethylaminoethylen-dextran polymer-drug conjugate nanoparticles. The DGA nanoparticles achieve ROS-responsive drug release. The DGA nanoparticles inhibit cytoplasmic translocation of nuclear HMGB1, thus modulate microglia to M2 phenotype. The DGA nanoparticles effectively alleviate the pathology of stroke, reduce infarct volume, and enhance neurogenesis.
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