MitoPG: An engineered biocompatible nanocarrier for drug delivery to neuronal mitochondria

Mitochondrial dysfunction is a key contributor to the pathogenesis of major neurodegenerative diseases such as Parkinson's disease. Targeted drug delivery to neuronal mitochondria is often limited by the inherent toxicity and inefficiency of drug carriers. Here we report the mitochondrial targeting ability of MitoPG, a novel nanocarrier based on dendritic polyglycerol (PG) conjugated with triphenylphosphonium (TPP⁺). Among a library of MitoPGs studied, MitoPG3 demonstrated superior mitochondrial localization and minimal cytotoxicity, without adverse effects on mitochondrial functions. Notably, it retained high mitochondrial targeting efficiency even under MPP⁺-induced mitochondrial dysfunction in neuronal cells. MitoPG 3 exhibited excellent blood brain permeability in vitro. To the best of our knowledge, this is the first report of a dendritic polymer-based nanocarrier with high mitochondrial localization and reduced toxicity and without impairing mitochondrial functions. These results highlight MitoPG as a safe and effective platform for delivering therapeutics to neuronal mitochondria, with the potential for clinical translation.