Neutrophil-Like Mitochondria Enable Blood-Brain Barrier Transmigration and Neuroprotection

Mitochondrial transplantation has emerged as a promising therapeutic strategy for neurological diseases associated with mitochondrial dysfunction. However, its application to central nervous system (CNS) disorders remains limited by the restrictive nature of the blood-brain barrier (BBB). Here, we report neutrophil-like mitochondria (nePM@Mito), engineered by coating isolated mitochondria with neutrophil plasma membranes to facilitate CNS delivery. By presenting neutrophil-derived surface adhesion molecules, nePM@Mito interact with endothelial receptors and recapitulate key features of neutrophil transendothelial migration, facilitating BBB crossing via endothelial exocytosis. In a mouse model of Parkinson's disease, intravenous administration of nePM@Mito leads to pronounced CNS accumulation and attenuation of oxidative stress. Delivered mitochondria restore mitochondrial function and increase tyrosine hydroxylase expression in dopaminergic neurons of the substantia nigra, resulting in elevated dopamine levels and improved motor performance. Notably, neutrophil membrane functionalization endows mitochondria with CNS-homing capability while preserving their intrinsic biological activity. The neutrophil-like mitochondrial delivery strategy provides a versatile platform for overcoming BBB limitations and offers a promising therapeutic approach for neurodegenerative diseases involving mitochondrial dysfunction.