A Dynamic Deferoxamine Polymer with Exceptional Performance in Mitochondrial Iron Depletion and Cytosolic Protein Delivery

Abstract Deferoxamine (DFO) is an FDA‐approved naturally occurring iron chelator commonly used to treat transfusion‐induced iron overload. The abundant and flexible hydroxamic acid groups in DFO enable exceptional iron binding capacity and high protein binding via hydrogen bonding interactions. However, the applications of DFO to sequester intracellular iron and to deliver proteins inside cells are limited due to poor membrane‐permeability. Herein, the fabrication of a dynamic DFO polymer is proposed to achieve robust intracellular protein delivery and efficient mitochondrial iron depletion. Specifically, DFO is grafted onto a polycatechol scaffold via dynamic catechol‐boronate chemistry. The obtained DFO polymer shows robust protein binding capacity, and the formed protein complexes show high resistance toward serum proteins. It effectively delivers various cargo proteins into cytosol of treated cells with maintained bioactivity. In addition, the polymer delivers DFO inside cells, and the released DFO efficiently depletes mitochondrial iron, which significantly inhibits mitochondrial oxidative phosphorylation and glycolysis. Remarkable synergistic cytotoxic effects are achieved when the DFO polymer is loaded with toxic proteins. This study provides a general strategy for facile preparation of bioactive polymer toward robust protein delivery, and the designed polymer can be a promising carrier for the delivery of protein therapeutics to treat cancer.