Research of brain targeting nano-metformin on cerebral ischemia-reperfusion injury based on microglial cell activation

Abstract

The polarization of microglia plays a crucial role in cerebral ischemia-reperfusion injury (CI/RI) and has garnered significant attention from researchers. M1-polarized microglia activation drives harmful inflammatory responses in neuronal cells. Although metformin can inhibit inflammatory reactions and improve CI/RI, it has significant toxic side effects. In this study, we designed a novel nanodrug delivery system, apoferritin nanocages encapsulating metformin (APO@Metformin), to address these issues. On the one hand, apoferritin nanocages are naturally available nanoparticles and widely present in biological systems, which possesses good biocompatibility and safety and reduces the toxic side effects of metformin. On the other hand, the small particle size of apoferritin nanocages enable them to have specific blood-brain barrier penetration to achieve brain targeting delivery. Animal experiments demonstrated that APO@Metformin improved CI/RI and reduced neuronal damage caused by inflammatory reactions. Furthermore, in vitro cell experiments showed that APO@Metformin not only could closely interact with transferrin receptors 1 (TfR1) expression in microglia to achieve superior brain targeting, but also inhibit the activity of M1 polarization and NLRP3 in microglia, thereby suppressing inflammatory responses in CI/RI and protecting neuronal cells.