Superoxide Dismutase‐Like Regulated Fe/Ppa@PDA/B for Synergistically Targeting Ferroptosis/Apoptosis to Enhance Anti‐Tumor Efficacy

Abstract The cell apoptosis pathway of sonodynamic therapy (SDT) is usually blocked, resulting in limited therapeutic efficacy, therefore, the development of new methods for sensitizing targeted ferroptosis and promoting apoptosis is of great significance to improve the anti‐tumor efficacy of SDT. Herein, mesoporous Fe 3 O 4 nanoparticles (NPs) are synthesized for loading pyropheophorbide‐a (ppa), surface‐coated by polydopamine (PDA) and further anchored with tumor‐targeting moieties of biotin to obtain Fe/ppa@PDA/B NPs. Fe/ppa@PDA/B displayes pH/ultrasound (US) responsive release properties, and magnetic resonance imaging (MRI) functions. Moreover, Fe 3 O 4 NPs of Fe/ppa@PDA/B as the Fe source for ferroptosis, enhances ferroptosis sensitivity by consuming glutathione (GSH) and producing hydroxyl radical (OH). The quinone groups of PDA layer on Fe/ppa@PDA/B own free electrons, which led to effective superoxide dismutase (SOD) action through superoxide anion (O 2 − ) disproportionation to hydrogen peroxide (H 2 O 2 ) and oxygen (O 2 ), thus, overcame hypoxia of SDT and promoted ·OH generation by Fe ions under US trigger, synergistically improves ferroptosis and apoptosis to enhance the anti‐tumor efficacy of SDT both in vitro and in vivo. The anti‐tumor strategy of synergistic apoptosis and ferroptosis induce by GSH depletion and self‐sufficient O 2 regulated by SOD provides a new idea for enhancing SDT efficacy.