Abstract

Parkinson’s disease (PD), the second leading cause of neurodegenerative disease worldwide, severely impairs the quality of life for the elderly. While current clinical treatments can alleviate symptoms, they fail to halt the progressive death of neurons, making the disease progression irreversible. This treatment bottleneck is largely attributed to the inability to effectively alleviate the “energy metabolism crisis” of dopaminergic neurons. Against this backdrop, piperine (Pip) has shown some neuroprotective potential, but its poor water solubility and inability to penetrate the blood–brain barrier (BBB) limit its application. This study aimed to develop RVG29 peptide-modified erythrocyte membrane biomimetic nanoparticles (RVG29-RM@Pip NPs) to address delivery challenges and explore metabolic intervention strategies. This system uses PLGA to load piperine, achieving immune escape and active brain targeting through biomimetic camouflage and RVG29 guidance. In vitro and in vivo experiments confirmed that these nanoparticles can efficiently penetrate the BBB, restore mitochondrial membrane potential, scavenge reactive oxygen species, and significantly improve motor dysfunction and neuronal loss in MPTP mice. Mechanistically, it remodels neuronal glycolysis and respiratory chain function by synergistically upregulating GLUT1, the rate-limiting enzyme PGK1, and mitochondrial complex I, restoring energy homeostasis and inhibiting apoptosis. This study not only constructed a brain-targeted delivery system but also revealed a mechanism and candidate approach for treating PD through metabolic remodeling.