Liu Chang, Zhou Weiping, Song Shuang, Li Ying, He Di, Han Wenzhao, Yu Cong
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
University of Science and Technology of China, Hefei 230026, China.
ACS Appl Mater Interfaces. 2025 Jul 16;17(28):40276-40287. doi: 10.1021/acsami.5c09829. Epub 2025 Jul 7.
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 HO, 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.
有效的肿瘤治疗仍然面临严峻挑战。声动力疗法（SDT）已被公认为光动力疗法的一种可行替代方法，它通过超声触发的声敏剂产生活性氧（ROS），具有更强的组织穿透能力且对皮肤损伤更小。然而，SDT的治疗效果常常受到癌细胞内在凋亡抗性的阻碍。此外，抗凋亡的癌细胞通常对铁死亡敏感，因此开发一种铁富集铁死亡策略对于联合凋亡 - 铁死亡抗肿瘤治疗至关重要。然而，肿瘤细胞常常通过上调自噬来对抗凋亡和铁死亡；因此，中断自噬降解过程对于提高治疗效果至关重要。相应地，我们通过整合铁、大黄酸和吲哚 - 3 - 乙酸（IAA）设计了一种金属 - 有机协同纳米治疗平台（Fe - Rh@IAA NPs），以靶向凋亡、铁死亡和自噬抑制。全身给药后，Fe - Rh@IAA NPs利用增强的渗透和滞留效应优先聚集在肿瘤部位。当受到超声照射时，Fe - Rh@IAA NPs通过SDT诱导凋亡，而铁离子通过产生活性氧和消耗谷胱甘肽诱导铁死亡。在高浓度HO的肿瘤微环境中，纳米颗粒的过氧化物酶样活性将IAA转化为有毒分子3 - 亚甲基 - 2 - 氧代吲哚，从而导致自噬活性受到抑制并最终导致肿瘤细胞死亡。此外，Fe - Rh@IAA NPs还可以提供磁共振成像能力，便于对肿瘤组织内物质积累进行无创实时监测。体外和体内研究表明，Fe - Rh@IAA NPs表现出优异的肿瘤杀伤能力和良好的生物安全性。这种三通道联合治疗策略为肿瘤治疗提供了新的见解和方法。
