Fe-Polyphenol Self-Assembled Nanoplatform for Sonodynamic-Ferroptosis-Autophagy Inhibition Synergistic Tumor Therapy

Effective tumor treatment still faces tough challenges. Sonodynamic therapy (SDT) has gained recognition as a viable substitute for photodynamic therapy, providing enhanced tissue penetration and reduced skin damage by generating reactive oxygen species (ROS) via ultrasound-triggered sonosensitizers. Nonetheless, the therapeutic efficacy of SDT is often hindered by the intrinsic apoptosis resistance of cancer cells. Additionally, apoptosis-resistant cancer cells often exhibit susceptibility to ferroptosis, making the development of an iron enrichment ferroptosis strategy crucial for the combined apoptosis–ferroptosis antitumor therapy. However, tumor cells often counteract apoptosis and ferroptosis by upregulating autophagy; thus, interrupting the autophagic degradation process is vital for the enhancement of the therapeutic outcome. Accordingly, we designed a metal–organic synergistic nanotherapeutic platform (Fe–Rh@IAA NPs) by incorporating iron, rhein, and indole-3-acetic acid (IAA) to target apoptosis, ferroptosis, and autophagy inhibition. Following systemic administration, Fe–Rh@IAA NPs were preferentially gathered at the tumor location, leveraging the enhanced permeability and retention effect. When exposed to ultrasonic irradiation, Fe–Rh@IAA NPs induced apoptosis via SDT, while the Fe ions induced ferroptosis through ROS production and glutathione depletion. At the tumor microenvironment with high concentrations of H 2 O 2, peroxidase-like activity of the nanoparticles converted IAA into the toxic molecule, 3-methylene-2-oxindole, which led to the suppression of autophagy activity and ultimately tumor cell death. In addition, Fe–Rh@IAA NPs could also provide magnetic resonance imaging capability, facilitating noninvasive real-time monitoring of material accumulation within tumor tissue. In vitro and in vivo studies demonstrated that Fe–Rh@IAA NPs exhibited excellent tumor-killing capabilities and favorable biosafety. This three-channel combined therapeutic strategy thus offers new insights and methodologies for tumor treatment.