Targeting mitochondrial dysfunction to quell neuroinflammation in central nervous system (CNS): a new strategy for treating CNS disease with nanomedicines

Neuroinflammation has emerged as an important pathogenic factor in central nervous system (CNS) disease, including various neurodegenerative diseases, brain injuries, and autoimmune conditions, affecting approximately 3 billion people worldwide. Mitochondrial dysfunction within neurovascular unit (NVU) cells not only initiates neuronal damage and blood-brain barrier (BBB) disruption but also critically reprograms immunometabolism, shifting microglia and infiltrating immune cells toward a pro-inflammatory, glycolysis-dominant state while impairing anti-inflammatory, oxidative phosphorylation-dependent functions. This metabolic rewiring fuels a vicious, self-amplifying cycle between mitochondrial impairment and sustained neuroinflammation. Consequently, targeting mitochondrial dysfunction has therefore emerged as a promising therapeutic strategy for controlling neuroinflammation. However, the double-membrane structure of mitochondria, coupled with the restrictive BBB, imposes formidable barriers to therapeutic delivery. Nanomedicine offers unprecedented opportunities. Advanced nanodrugs, engineered with mitochondrial-targeting ligands, stimuli-responsive materials, or biomimetic coatings, enable precise delivery of therapeutics directly to impaired mitochondria within the CNS. This review summarizes recent advances in mitochondrial dysfunction-induced neuroinflammation, highlights emerging nanotechnology-based mitochondrial targeting strategies in various CNS diseases, and discusses the existing challenges and future perspectives for translating these approaches into effective CNS therapies.