Mitochondria in brain diseases: Bridging structural-mechanistic insights into precision-targeted therapies

Mitochondria, as central regulators of cell fate, signaling, metabolism, and tissue homeostasis, are critical in the pathogenesis of brain diseases. Recent advancements in nanomedicine delivery technologies have elucidated mitochondrial heterogeneity, intercellular interactions, and downstream therapeutic mechanisms with enhanced precision. These developments underscore the importance of exploring mitochondrial regulatory mechanisms within the context of specific brain diseases. However, the delivery of mitochondria-targeted therapies across the blood-brain barrier (BBB) remains a clinical obstacle, necessitating comprehensive investigations into the BBB's impact on these therapies. Herein, we systematically examine the diverse phenotypes and functional plasticity of mitochondria in the regulatory mechanisms of brain diseases. We also delve into the novel insights provided by nano-targeted therapies, emphasizing the interplay between mitochondria and oxidative stress across various etiologies and disease features, particularly in gliomas, neurodegenerative diseases, ischemic stroke, and acute brain injuries. Additionally, we highlight preclinical and clinical mitochondrial-targeting strategies and discuss their translational implications.