二甲双胍纳米颗粒通过改善线粒体功能障碍和抑制NLRP3激活减轻脑缺血再灌注损伤。

IF 6 2区医学 Q2 MATERIALS SCIENCE, BIOMATERIALS

Materials Science & Engineering C-Materials for Biological Applications Pub Date : 2025-09-11 DOI:10.1016/j.bioadv.2025.214507

Lin Deng , Ting Cai , Jiayu Li , Yinfei Song , Sheng Guo , Tao Tao

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引用次数: 0

摘要

背景：脑缺血再灌注损伤（CIRI）是一种严重的疾病，缺乏有效的治疗方法。在CIRI后，小鼠皮层的小胶质细胞显示CD44的高表达，这为开发靶向给药系统治疗缺血性脑损伤提供了潜在的靶点。目的：设计缺血性脑损伤靶向给药系统，探讨缺血性脑损伤的分子机制。方法：设计透明质acid-PEG-DSPE@metformin （HA@MET）纳米颗粒特异性靶向小胶质细胞上的CD44受体。使用HA@MET干预CIRI小鼠模型，然后测量梗死面积和神经学评分。此外，我们还对自噬相关蛋白（Beclin-1、Atg5、Sirt3）的表达、活性氧（ROS）的产生、NLRP3炎症小体的激活以及相关炎症因子（Caspase-1、IL-6、IL-1β）的释放进行了实验。结果：在CIRI小鼠模型中，HA@MET治疗导致梗死面积显著减少，神经学评分改善，表明对缺血性脑损伤有很强的治疗作用。在机制上，HA@MET抑制了关键自噬蛋白Beclin-1和Atg5的表达，同时增加了Sirt3蛋白的表达。这一作用减轻了线粒体过度自噬，促进了受损线粒体的清除。HA@MET进入小胶质细胞后释放二甲双胍，减少ROS的产生，抑制NLRP3炎症小体的激活，导致炎症因子（Caspase-1、IL-6、IL-1β）浓度降低，减轻CIRI相关的炎症反应。结论：本研究为缺血性脑损伤的治疗提供了新的视角和潜在的治疗靶点。HA@MET作为一种靶向给药系统，通过多种机制，包括调节线粒体自噬和抑制炎症，显示出治疗CIRI的希望。

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Metformin nanoparticles mitigate cerebral ischemia reperfusion injury by improving mitochondrial dysfunction and inhibiting NLRP3 activation

Background

Cerebral ischemia reperfusion injury (CIRI) is a serious condition that lacks highly effective treatment methods. After CIRI, microglia in the cortex of mice show high expression of CD44, which offers a potential target for the development of targeted drug-delivery systems to treat ischemic brain injury.

Objective

This study aimed to design a targeted drug-delivery system for ischemic brain injury, and explore the underlying molecular mechanisms on CIRI.

Methodology

Hyaluronic acid-PEG-DSPE@metformin (HA@MET) nanoparticles were designed to specifically target the CD44 receptor on microglia. HA@MET was used to intervene in a CIRI mouse model, and then the infarct size and neurological scores were measured. Moreover, experiments on the expression of autophagy-related proteins (Beclin-1, Atg5, Sirt3), the production of reactive oxygen species (ROS), the activation of the NLRP3 inflammasome and the release of associated inflammatory factors (Caspase-1, IL-6, IL-1β) were performed.

Results

In the CIRI mouse model, HA@MET treatment led to a significant reduction in infarct size and an improvement in neurological scores, indicating a strong therapeutic effect on ischemic brain injury. Mechanistically, HA@MET inhibited the expression of key autophagy proteins Beclin-1 and Atg5, while increasing the expression of Sirt3 protein. This action alleviated excessive mitochondrial autophagy and promoted the clearance of damaged mitochondria. After entering microglia, HA@MET released metformin, which decreased ROS production and inhibited the activation of the NLRP3 inflammasome, resulting in reduced concentrations of inflammatory factors (Caspase-1, IL-6, IL-1β) and alleviating the inflammatory responses associated with CIRI.

Conclusions

This study provides new perspectives and potential therapeutic targets for the treatment of ischemic brain injury. HA@MET, as a targeted drug-delivery system, shows promise in treating CIRI through multiple mechanisms, including regulating mitochondrial autophagy and inhibiting inflammation.

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来源期刊

Materials Science & Engineering C-Materials for Biological Applications 工程技术-材料科学：生物材料

CiteScore

17.80

自引率

0.00%

发文量

501

审稿时长

27 days

期刊介绍： Biomaterials Advances, previously known as Materials Science and Engineering: C-Materials for Biological Applications (P-ISSN: 0928-4931, E-ISSN: 1873-0191). Includes topics at the interface of the biomedical sciences and materials engineering. These topics include: • Bioinspired and biomimetic materials for medical applications • Materials of biological origin for medical applications • Materials for "active" medical applications • Self-assembling and self-healing materials for medical applications • "Smart" (i.e., stimulus-response) materials for medical applications • Ceramic, metallic, polymeric, and composite materials for medical applications • Materials for in vivo sensing • Materials for in vivo imaging • Materials for delivery of pharmacologic agents and vaccines • Novel approaches for characterizing and modeling materials for medical applications Manuscripts on biological topics without a materials science component, or manuscripts on materials science without biological applications, will not be considered for publication in Materials Science and Engineering C. New submissions are first assessed for language, scope and originality (plagiarism check) and can be desk rejected before review if they need English language improvements, are out of scope or present excessive duplication with published sources. Biomaterials Advances sits within Elsevier''s biomaterials science portfolio alongside Biomaterials, Materials Today Bio and Biomaterials and Biosystems. As part of the broader Materials Today family, Biomaterials Advances offers authors rigorous peer review, rapid decisions, and high visibility. We look forward to receiving your submissions!