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 H₂O₂, 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.