Biomimetic Nanoparticles Enhance Recovery of Movement Disorders in Parkinson's Disease by Improving Microglial Mitochondrial Homeostasis and Suppressing Neuroinflammation.

Abstract

Neuroinflammation is a key risk factor for cognitive impairment, and microglia are the main drivers. Metformin has been shown to suppress inflammation and reduce microglial activation, protecting neurons from damage. However, its clinical efficacy is limited by low bioavailability and metabolic challenges, especially in terms of precise delivery to specific targets. To overcome this problem, we developed biomimetic microglial nanoparticles (MePN@BM) to enhance the targeted delivery and bioavailability of metformin. Through homologous targeting, the delivery efficiency of drugs in the inflammatory site of Parkinson's disease was enhanced to improve the therapeutic effect. The results showed that MePN@BM effectively delivers metformin to the brain, promotes autophagy, restores mitochondrial membrane potential, and reduces oxidative stress. In a Parkinson's disease (PD) mouse model, MePN@BM improved motor function, repaired dopaminergic neurons, and cleared α-synuclein aggregates. Notably, transcriptome analysis revealed enriched inflammation-related pathways, and immunofluorescence showed that PD mice treated with MePN@BM had higher levels of anti-inflammatory factors and lower levels of pro-inflammatory factors. Therefore, it provides a promising strategy for the treatment of inflammation-mediated motor dysfunction.