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

Abstract

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.