Polydopamine Nanoparticles as a Potential Non-Pharmaceutical Antioxidant Tool against Mitochondrial Disorders

Mitochondrial disorders are hereditary diseases caused by mutations in nuclear or mitochondrial DNA that impair organelle function. Key features include excessive production of reactive oxygen species (ROS), mitochondrial abnormalities, and metabolic dysfunctions. Systemically, these defects can lead to severe conditions affecting the central nervous system, muscles, heart, and gastrointestinal tract. Organic antioxidants such as idebenone and resveratrol have been explored as potential treatments; in the framework of nanotechnological antioxidants, polydopamine nanoparticles (PDNPs), derived from the oxidative self-polymerization of dopamine, are highly biocompatible, biodegradable, easy to functionalize, and possess potent ROS-scavenging and photothermal properties. In this study, we investigated PDNPs as a nonpharmaceutical therapy for mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and progressive external ophthalmoplegia (PEO). PDNPs were evaluated in fibroblasts from healthy donors and patients with MELAS and PEO. Molecular characterization was performed via proteomic analysis, followed by assessment of PDNP biocompatibility, internalization, intracellular localization, and antioxidant effects. Their protective activity was also confirmed in vivo, exploiting zebrafish embryos. Our findings demonstrate that PDNPs effectively protect cells from ROS-induced damage, oxidative stress, apoptosis, and mitochondrial dysfunction. Additionally, PDNPs were able to preserve zebrafish embryos against pro-oxidative stimuli. Overall, this work highlights the potential of polydopamine nanostructures as promising therapeutic tools for mitigating the molecular hallmarks of mitochondrial disorders and supporting future clinical applications.