Research progress and prospect in mitochondrial-targeted therapy

Background As the core organelles of eukaryotic cells, mitochondria play an indispensable role in physiological processes such as energy production and signal transduction. Their functional abnormalities are closely associated with the onset and progression of diverse diseases, including cancers, neurodegenerative disorders, metabolic diseases, and inherited mitochondrial diseases. However, the therapeutic objectives differ fundamentally across these conditions: in neurodegenerative, metabolic, and inherited mitochondrial diseases, the goal is to restore mitochondrial bioenergetics, redox balance, and quality control; conversely, in cancers, the objective is often to disrupt mitochondrial homeostasis—exploiting the reliance of tumor cells on glycolysis, elevated reactive oxygen species (ROS), and anti-apoptotic defenses to trigger metabolic catastrophe and cell death. Current treatments for mitochondrial-related diseases still face technical challenges, including insufficient targeting efficiency and limited mechanistic diversity, necessitating the development of precise and effective targeted therapeutic strategies tailored to each paradigm. Technology This study systematically reviews three core technologies for mitochondrial-targeted therapy: firstly, small-molecule drugs targeting mitochondrial metabolism and ROS regulation (e.g., idebenone, imeglimin); secondly, nanoscale targeted delivery systems based on materials such as liposomes, micelles, and metal-organic frameworks, achieving mitochondrial-specific enrichment through surface modification; thirdly, emerging mitochondrial transplantation techniques restore damaged cellular function by infusing healthy mitochondria. All these technologies must meet critical requirements, including targeting specificity, biological stability, and efficient delivery. This review evaluates mitochondrial-targeting as a therapeutic strategy rather than a biological subject. We evaluate all strategies using a five-domain technical framework encompassing design logic, delivery efficiency, biosafety, manufacturing scalability and regulatory translatability—moving beyond conventional mitochondrial pathology reviews to deliver a translational design guide for clinical translation. Results Preclinical and clinical studies indicate that small-molecule drugs demonstrate symptomatic improvement in conditions such as optic neuropathy and muscular dystrophy; nanosystems significantly enhance mitochondrial drug delivery efficiency, amplifying therapeutic outcomes such as chemotherapy efficacy; mitochondrial transplantation has demonstrated preliminary feasibility and efficacy signals in early-phase studies for conditions including cardiac ischemia-reperfusion injury and mitochondrial DNA deletion syndromes; however, definitive therapeutic efficacy awaits confirmation in adequately powered controlled trials. This review provides a comprehensive reference for fundamental research and clinical translation in mitochondrial-targeted therapies, charting new pathways for precision treatment of related diseases.