Mitochondria-Targeted Nanosystems in the Treatment of Central Nervous System Diseases

Xiaolan Zhang,1,* Jiahui Chen,2,* Bingjie Wan,1 Yanrong Zheng,1 Xiaojie Chen1 1Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences, First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 2College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanrong Zheng, Email [email protected] Xiaojie Chen, Email [email protected]: Mitochondrial dysfunction represents a pivotal pathological mechanism underlying diverse diseases, particularly those affecting the central nervous system (CNS). Consequently, therapeutic strategies capable of effectively restoring mitochondrial function hold significant promise for treating CNS disorders. Nanotechnology has emerged as a powerful platform in this endeavor, leveraging the modifiability, controllability, and targeting capabilities of nanosystems to intervene at the mitochondrial level. This review delineates the critical role of mitochondrial integrity in CNS pathophysiology and summarizes key mitochondria-targeting strategies, including small-molecule ligands, mitochondrial-penetrating peptides, mitochondrial membrane-derived vesicles, and biomimetic membrane coatings. We also discuss the efficacy of mitochondria-targeted nanosystems in rescuing mitochondrial dysfunction across major CNS conditions, exemplified by neurodegenerative diseases, brain tumors, ischemic stroke, and traumatic brain injury. Ultimately, this review also points out current translational challenges and future research directions pivotal for advancing mitochondrial nanomedicine. Collectively, this work synthesizes progress in mitochondrial nanotherapeutics, highlighting their transformative potential while outlining critical barriers and opportunities for clinical translation in CNS disorders. Keywords: Mitochondrial dysfunction, Mitochondria-targeted therapy, Nanosystems, Drug delivery