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Herein, this work designs a mitochondria\u2010targeted micelle CsA\u2010TK\u2010SS\u201031 (CTS) to block the progression of AD by simultaneously alleviating mitochondrial dysfunction in microglia and neurons. The mitochondria\u2010targeted peptide SS\u201031 drives cyclosporin A (CsA) to penetrate the blood\u2010brain barrier (BBB) and delivers CsA to mitochondria of microglia and neurons in the brains of 5 \u00d7 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\u201031 is broken and CsA and SS\u201031 are released while consuming ROS in the microenvironment. The released CsA and SS\u201031 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 \u00d7 FAD mice. Ultimately, the neuroinflammation and cognitive impairment of 5 \u00d7 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.<\/jats:p>","DOI":"10.1002\/smll.202408581","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T10:55:06Z","timestamp":1734951306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["The Mitochondria\u2010Targeted Micelle Inhibits Alzheimer's Disease Progression by Alleviating Neuronal Mitochondrial Dysfunction and Neuroinflammation"],"prefix":"10.1002","volume":"21","author":[{"given":"Wenqiang","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy Air Force Medical University  Xi'an 710032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daozhou","family":"Liu","sequence":"additional","affiliation":[{"name":"Department 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