Self-Hijacking Ferritin Nanostructures for Targeted Delivery of Iron to Enhance Synergistic Anticancer Therapy

Iron ions are effective agents for inducing cellular ferroptosis, indicating great potential for cancer therapy. However, cells possess a robust mechanism to regulate iron ions within a reasonable range. Administering excessive iron can enhance ferroptosis and will also cause potential adverse effects. To overcome this limitation, we engineered a 12 nm ferritin nanocage with precisely controlled architecture─a naturally occurring nanocarrier exhibiting specific TfR1-targeting capability to enhance the cellular internalization efficiency. Furthermore, protoporphyrin IX (PPIX), a sonosensitizer, was encapsulated within the 8 nm inner cavity of ferritin to generate a sonodynamic therapeutic (SDT) effect. Upon exposure to ultrasound irradiation, the activated PPIX generates reactive oxygen species (ROS) within the ferritin cavity, which degrade the nanocage structure, release free iron ions, and subsequently trigger ferroptosis to inhibit tumor growth. Additionally, the liberated iron reacts with excess intracellular H 2 O 2 to produce O 2, thereby enhancing the efficacy of SDT. In summary, this study introduces a self-destroying ferritin system for highly efficient targeted delivery of iron ions, offering a promising strategy for synergistic ferroptosis-sonodynamic antitumor therapy.