Mitochondria‐Directed Redox Phospholipid Polymers for Cancer Therapy

ABSTRACT Intracellular redox regulation is increasingly recognized as compartment‐specific, with each organelle maintaining a distinct redox environment. Mitochondria are a major source of reactive oxygen species (ROS), and many cancer cells exhibit elevated basal ROS levels, making mitochondrial redox modulation an attractive strategy for redox‐based cancer therapy. However, efficient mitochondrial delivery of redox‐active agents remains challenging. Small‐molecule redox agents often require hydrophobicity that compromises their water solubility and increases their non‐specific toxicity. Although synthetic polymers improve solubility and biocompatibility, they are predominantly taken up via endocytosis, which often requires additional elements for endosomal escape to achieve efficient cytosolic access and mitochondrial delivery. In this study, we developed mitochondria‐directed phospholipid polymers based on 2‐methacryloyloxyethyl phosphorylcholine (MPC) and redox‐active ferrocene using a simple copolymerization strategy. We leveraged the cell‐penetrating characteristics of amphiphilic MPC copolymers bearing hydrophobic ferrocene units to access the cytosol and introduced a mitochondria‐directed motif by copolymerizing a triphenylphosphonium (TPP)‐containing monomer. The TPP‐bearing polymer exhibited higher in vitro anticancer activity than the non‐directed polymer in CT26 mouse colon cancer cells. Confocal co‐localization analysis revealed that the non‐directed polymer was widely distributed throughout the cells, whereas the TPP‐bearing polymer showed significantly higher mitochondrial co‐localization. The TPP‐bearing polymer also induced higher intracellular ROS levels than the non‐directed polymer. Moreover, intratumoral administration of the TPP‐bearing polymer significantly suppressed CT26 tumor growth in mice. Overall, this study provides a simple design strategy for organelle‐directed redox‐active polymers toward redox‐based cancer therapy.