Abstract
Demyelination is a common feature of neuroinflammatory and degenerative diseases of the central nervous system (CNS), such as multiple sclerosis (MS). It is often linked to disruptions in intercellular communication, bioenergetics and metabolic balance accompanied by mitochondrial dysfunction in cells such as oligodendrocytes, neurons, astrocytes, and microglia. Although current MS treatments focus on immunomodulation, they fail to stop or reverse demyelination's progression. Recent advancements highlight intercellular mitochondrial exchange as a promising therapeutic target, with potential to restore metabolic homeostasis, enhance immunomodulation, and promote myelin repair. With this review we will provide insights into the CNS intercellular metabolic decoupling, focusing on the role of mitochondrial dysfunction in neuroinflammatory demyelinating conditions. We will then discuss emerging cell-free biotherapies exploring the therapeutic potential of transferring mitochondria via biogenic carriers like extracellular vesicles (EVs) or synthetic liposomes, aimed at enhancing mitochondrial function and metabolic support for CNS and myelin repair. Lastly, we address the key challenges for the clinical application of these strategies and discuss future directions to optimize mitochondrial biotherapies. The advancements in this field hold promise for restoring metabolic homeostasis, and enhancing myelin repair, potentially transforming the therapeutic landscape for neuroinflammatory and demyelinating diseases.