Breast cancer remains one of the most common malignancies in women worldwide, and although overall survival has improved in recent decades, metastatic breast cancer—especially bone metastasis—continues to be a major cause of poor prognosis and mortality. Current treatments are still largely focused on controlling primary tumors, with limited efficacy against metastatic lesions, which has driven growing interest in therapeutic strategies that can both eradicate tumors and reprogram the immunosuppressive tumor microenvironment. "Sonodynamic therapy (SDT), with its deep tissue penetration and strong spatiotemporal controllability, has emerged as a promising approach for solid tumor treatment; however, currently available multifunctional sonosensitizers still face key limitations, including poor biodegradability in inorganic systems and limited multifunctionalization in organic small molecules." said the author Ming Wu, a researcher at Gongli Hospital of Pudong New Area, "Against this backdrop, covalent organic frameworks (COFs), owing to their tunable structures, favorable biocompatibility, and functionalization potential, are increasingly regarded as promising platforms for next-generation multifunctional sonodynamic therapy."
In this study, the authors developed ferrocene-modified nanoscale covalent organic frameworks (mCOFs) through a top-down strategy by reacting microscale COFs with aminoferrocene, thereby achieving both nanosizing and Fenton-like catalytic functionality. Under ultrasound irradiation, the platform was designed to generate singlet oxygen, while the Fe2+ centers in ferrocene catalyzed the conversion of endogenous H2O2 in the tumor microenvironment into hydroxyl radicals, enabling amplified oxidative damage through a dual ROS mechanism. The authors first performed systematic characterization of particle size, dispersibility, crystalline structure, and ROS-generation capability, and then evaluated cellular uptake, intracellular ROS production, apoptosis, ferroptosis, and immunogenic cell death-related effects in 4T1 breast cancer cells. Finally, using orthotopic breast tumor and bone metastasis mouse models together with intravenous administration and ultrasound activation, they assessed the therapeutic performance of this nanoplatform in suppressing primary tumors, remodeling the tumor immune microenvironment, and inhibiting bone metastasis.
The results showed that the engineered mCOFs could markedly amplify oxidative damage under ultrasound activation and simultaneously induce both apoptosis and ferroptosis in breast cancer cells. Compared with the controls, mCOF + US exhibited substantially enhanced singlet oxygen and hydroxyl radical generation, leading to a pronounced increase in intracellular ROS. In vitro, treatment with mCOF + US reduced 4T1 cell viability to 24.3% and increased the apoptosis rate to 84.51%, accompanied by strong lipid peroxidation, indicating a synergistic tumoricidal effect mediated by combined apoptosis and ferroptosis. In addition, this treatment triggered robust immunogenic cell death, as reflected by an increase in ATP release from 0.37 nM to 1.75 nM, an elevation in dendritic cell maturation from 5.27% to 23.6%, and 3.81-fold and 3.14-fold increases in IL-6 and TNF-α levels, respectively. In vivo, intravenously injected mCOFs showed high tumor accumulation at 12 h post-injection, and ultrasound activation led to marked inhibition of orthotopic tumor growth while alleviating osteolytic destruction associated with bone metastasis, as evidenced by improved bone volume fraction and bone mineral density. Further immune analyses revealed increased infiltration of mature DCs, CD4+ and CD8+ T cells, NK cells, and IFN-γ-positive CD8+ T cells, suggesting that this strategy not only directly kills tumor cells but also remodels the immunosuppressive tumor microenvironment to synergistically inhibit breast cancer progression and bone metastasis.
Overall, this study developed a ferrocene-modified nanoscale COF-based sonodynamic platform that integrates ultrasound-triggered ROS generation with Fenton-like catalysis, ferroptosis induction, and immune microenvironment remodeling, thereby achieving synergistic inhibition of both primary breast tumors and bone metastasis. The significance of this work lies in the fact that it not only provides a biocompatible and multifunctional organic nanotherapeutic system with potent antitumor activity, but also demonstrates that combining sonodynamic therapy with immunomodulation may help overcome the traditional limitation of therapies that mainly focus on primary tumor control while offering a broader strategy for metastatic intervention. "By introducing therapeutically active ferrocene moieties during the nanosizing of COFs, we provide a new design strategy for multifunctional sonosensitizers and further demonstrate the promising potential of nanomedicine-based combination therapies for suppressing breast cancer progression and bone metastasis." said Ming Wu.
Authors of the paper include Ming Wu, Yiqing Zeng, JianGang Chen, Zhen Yang, Siyuan Song, Rongkai Yan, Taofik Al Hassan, and Yan Zhang.
The authors acknowledge funding support from the Scientific Research Project of Shanghai Municipal Health Commission (202340056), Key Discipline Construction Project of Pudong Health Commission of Shanghai (PWZxk2022-09), New Quality Clinical Specialty Program of High-end Medical Disciplinary Construction in Shanghai Pudong New Area (81772383), National Natural Science Foundation of China (81772383), Shanghai Pudong New Area Gongli Hospital National Foundation Incubation Fund (2024GPY-B02), and Youth Fund Project of Gongli Hospital, Pudong New Area, Shanghai (2022YQNJJ-09).
The paper, "Ferrocene-Modified Nanoscale Covalent Organic Frameworks for Ferroptosis-Based Sonodynamic Therapy Inhibit Breast Cancer and Its Bone Metastasis" was published in the journal Cyborg and Bionic Systems on Mar 23, 2026, at https://doi.org/10.34133/cbsystems.0490.
