The Mitochondria‐Targeted Micelle Inhibits Alzheimer's Disease Progression by Alleviating Neuronal Mitochondrial Dysfunction and Neuroinflammation

Abstract Mitochondrial dysfunction plays an important role in neuroinflammation and cognitive impairment in Alzheimer's disease (AD). Herein, this work designs a mitochondria‐targeted micelle CsA‐TK‐SS‐31 (CTS) to block the progression of AD by simultaneously alleviating mitochondrial dysfunction in microglia and neurons. The mitochondria‐targeted peptide SS‐31 drives cyclosporin A (CsA) to penetrate the blood‐brain barrier (BBB) and delivers CsA to mitochondria of microglia and neurons in the brains of 5 × FAD mice. Under the high level of reactive oxygen species (ROS) environment in damaged mitochondria of microglia and neurons, the linker (thioketal, TK) between CsA and SS‐31 is broken and CsA and SS‐31 are released while consuming ROS in the microenvironment. The released CsA and SS‐31 synergistically restore the mitochondrial membrane potential and the balance between the fission and fusion of mitochondria, which subsequently protect neurons from apoptosis and reduce the activation of microglia in the brains of 5 × FAD mice. Ultimately, the neuroinflammation and cognitive impairment of 5 × FAD mice are ameliorated. This research provides a synergistic treatment strategy for AD through alleviating mitochondrial dysfunction to reduce neuroinflammation and restore the function of neurons simultaneously.