Neutrophil-Biomimetic “Nanobuffer” for Remodeling the Microenvironment in the Infarct Core and Protecting Neurons in the Penumbra via Neutralization of Detrimental Factors to Treat Ischemic Stroke
Neutrophil-Biomimetic “Nanobuffer” for Remodeling the Microenvironment in the Infarct Core and Protecting Neurons in the Penumbra via Neutralization of Detrimental Factors to Treat Ischemic Stroke
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中性粒细胞仿生“纳米缓冲液”用于重塑梗塞核心微环境并通过中和有害因素保护半暗带神经元来治疗缺血性中风
DOI：
10.1021/acsami.2c09020
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发表时间：
2022
影响因子：
9.5
通讯作者：
Jun Chen
中科院分区：
文献类型：
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作者：
Shanshan Liu;Jianpei Xu;Yipu Liu;Yang You;Laozhi Xie;Shiqiang Tong;Yu Chen;Kaifan Liang;Songlei Zhou;Fengan Li;Zhuang Tang;Ni Mei;Huiping Lu;Xiaolin Wang;Xiaoling Gao;Jun Chen
高水平的ROS和炎性细胞因子等有害因子在梗死灶中心堆积，并侵蚀到可挽救的半暗带，是卒中缺血再灌注损伤的重要病理环节。很少有神经保护剂可以重塑梗塞核心的敌意微环境，因为它无法干扰死亡或生物功能不活跃的濒临死亡的细胞。即使缺血再灌注损伤也可通过药物在半影区暂时减轻；来自核心的有害因素的侮辱仍随着药物的代谢和清除而不断侵蚀半影区。在此，提出了一种名为纳米缓冲区的策略，以中和有害因素并缓冲对半影区的破坏性侵蚀。受中性粒细胞对梗塞核心的趋向性和对炎症细胞因子的亲和力的启发，聚乳酸-乙醇酸(PLGA)纳米颗粒被中性粒细胞膜包裹以靶向梗塞核心并吸收炎症细胞因子；表面修饰α-硫辛酸，负载大麻二醇分别用于清除ROS和神经保护，以构建纳米缓冲液的基本单元。这种纳米缓冲剂通过中和有害因子和大麻二醇诱导的神经保护作用在梗死区发挥综合作用。此外，在体内，通过动态ROP(开环聚合)诱导的紧密相邻单元之间的膜交叉融合，可能会增强纳米缓冲液。系统评估显示，与未经治疗的卒中大鼠组相比，中风核心和半影区的有害因素显著减少，梗死体积缩小，神经恢复得到改善。
High level of detrimental factors including reactive oxygen species (ROS) and inflammatory cytokines accumulated in the infarct core and their erosion to salvageable penumbra are key pathological cascades of ischemia-reperfusion injury in stroke. Few neuroprotectants can remodel the hostile microenvironment of the infarct core for the failure to interfere with dead or biofunctionally inactive dying cells. Even ischemia-reperfusion injury is temporarily attenuated in the penumbra by medications; insults of detrimental factors from the core still erode the penumbra continuously along with drug metabolism and clearance. Herein, a strategy named nanobuffer is proposed to neutralize detrimental factors and buffer destructive erosion to the penumbra. Inspired by neutrophils' tropism to the infarct core and affinity to inflammatory cytokines, poly(lactic-co-glycolic acid) (PLGA) nanoparticles are coated with neutrophil membrane to target the infarct core and absorb inflammatory cytokines; α-lipoic acid is decorated on the surface and cannabidiol is loaded for ROS scavenging and neuroprotection, respectively, to construct the basic unit of the nanobuffer. Such a nanobuffer exerts a comprehensive effect on the infarct area via detrimental factor neutralization and cannabidiol-induced neuroprotection. Besides, the nanobuffer can possibly be enhanced by dynamic ROP (ring-opening-polymerization)-induced membrane cross-fusion among closely adjacent units in vivo. Systematic evaluations show significant decrease of detrimental factors in the core and the penumbra, reduced infarct volume, and improved neurological recovery compared to the untreated group of stroke rats.