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

Sep 17, 2025Biomaterials advances

Metformin nanoparticles may reduce brain damage after blood flow returns by improving cell energy function and lowering inflammation

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Abstract

HA@MET treatment resulted in a significant reduction in infarct size and improved neurological scores in a mouse model of cerebral ischemia reperfusion injury.

Microglia in the cortex of mice exhibit high expression of CD44 after cerebral ischemia reperfusion injury.
HA@MET nanoparticles are designed to target the CD44 receptor on microglia for drug delivery.
HA@MET treatment inhibits the expression of autophagy-related proteins Beclin-1 and Atg5 while increasing Sirt3 protein expression.
This treatment reduces excessive mitochondrial autophagy and promotes the clearance of damaged mitochondria.
HA@MET decreases reactive oxygen species production and inhibits the activation of the NLRP3 inflammasome.
The intervention leads to reduced levels of inflammatory factors such as Caspase-1, IL-6, and IL-1β.

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

Abstract

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