Versatile Nanotherapeutics for Enhancing Sonodynamic Therapy/Chemotherapy of Thyroid Cancer through Remodeling Tumor Microenvironment and Synergistic Reactive Oxygen Species Augment

Anaplastic thyroid carcinoma (ATC), as the most malignant pathological type, is prone to local invasion and even distant metastasis with a poor prognosis and a high recurrence rate. Herein, we developed an iron-based metal organic framework (FL@M) as an effective sonosensitizer and biomimetic nanocarrier through the incorporation of lenvatinib (Len) and further coating with homologous tumor cell membranes, achieving the synergistic sonodynamic therapy/chemotherapy for ATC. With the homologous tumor membrane camouflage, FL@M nanoparticles exhibited good biocompatibility, drug loading, and excellent tumor targeting ability both in vitro and in vivo. After absorption, FL@M was decomposed and released Len and Fe³⁺/Fe²⁺. Under ultrasound irradiation, FL@M exhibited excellent sonodynamic effects, rapidly generating a large amount of reactive oxygen species (ROS), which induced oxidative stress and cell apoptosis. In addition, Fe³⁺/Fe²⁺ had good catalase enzyme activity and peroxidase enzyme activity, which could catalyze H₂O₂ to produce O₂ and cytotoxic •OH, respectively, further enhancing the efficacy of sonodynamic therapy (SDT). Moreover, Len exerted a synergistic effect by promoting ROS production during SDT at a lower concentration, which could decrease the occurrence of side effects. In summary, our findings demonstrated that FL@M is a safe and effective metal-organic framework-based nanoplatform to inhibit tumor proliferation, recurrence, and metastasis, offering a promising SDT/chemotherapy combination strategy on thyroid cancer.