Nanomaterial-Mediated Targeting of Mitochondrial Metabolism: Strategies and Applications in Cancer Therapy

Yue Hu,1,2 Peichen Xie,2 Jialin Li,2 Rui Liu,2 Haotong Wang,2 Zhicheng Wang,2 Chunyan Liu1 1Department of Radiology, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 2NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Zhicheng Wang, Email [email protected] Chunyan Liu, Email [email protected]: Mitochondria serve as cellular powerhouses and function as central hubs for oxidative metabolism and signaling regulation. These organelles produce ATP primarily through oxidative phosphorylation (OXPHOS), thereby fueling cellular growth and function. In cancer, metabolic reprogramming drives malignant progression, with mitochondria playing a pivotal role. To meet heightened energy and biosynthetic demands, cancer cells modulate mitochondrial OXPHOS activity while enhancing fatty acid oxidation and amino acid metabolism, thereby maintaining redox balance and supporting survival and proliferation. Targeting mitochondrial metabolism with nanomaterials has emerged as a promising strategy for cancer therapy. This review covers advances from 2018– 2025, encompassing lipid-based, polymeric, peptide-functionalized, and stimuli-responsive nanocarriers. By employing nanocarriers to deliver metabolic inhibitors or chemotherapeutic agents precisely to mitochondria, this approach can disrupt energy metabolism, impair redox homeostasis, or induce apoptosis in tumor cells. Such targeted intervention not only enhances chemotherapy efficacy but also synergizes with radiotherapy and immunotherapy, offering a potential route to overcome resistance. Despite its considerable promise, several challenges remain in the nanomaterial-based targeting of mitochondrial metabolism, including optimization of targeting efficiency and biosafety. Future efforts should focus on refining these aspects to accelerate the clinical translation of precise mitochondrial metabolism–directed therapies.Keywords: nanomaterials, mitochondrion, metabolism, cancer therapy, mitochondrial membrane potential, reactive oxygen species