Polynorepinephrine nanoagent enables targeted mitochondrial delivery for enhanced tumor therapy through ferroptosis

The current drug delivery systems based on ferroptosis, which induce oxidative stress, are generally limited by the random generation and distribution of reactive oxygen species (ROS) without targeted delivery in the tumor microenvironment, resulting in unsatisfactory therapeutic outcomes. To address this issue, mitochondria were identified as ideal targets for anti-tumor treatment to enhance ROS attacks through the precise delivery of nanoagents. In this study, we developed a nanoagent named PNE-PEG-TPP-Fe by chelating triphenylphosphine (TPP)-modified polynorepinephrine (PNE) with Fe^2 + . This nanoagent significantly enhanced ferroptosis of tumor cells by mitochondria targeting and increasing H₂O₂ concentration in mitochondria. Specifically, the lipophilic cationic TPP facilitates the nanoparticle translocation across both the cellular and mitochondrial membranes, enabling precise accumulation within the mitochondria. The PNE carrier can generate H₂O₂ and improve H₂O₂ level in mitochondria by catechol oxidation. Moreover, this nanoagent induces an excessive influx of Fe²⁺ into mitochondria, generating a substantial amount of ·OH by Fenton reaction, which can attack the mitochondrial membrane, disrupt the ferroptosis defense system in mitochondria, and enhance lipid peroxides generation and accumulation. This study underscores the potential benefits of selectively targeting mitochondria to enhance anti-cancer effects mediated by ferroptosis and has valuable prospect for anti-tumor therapies.