# Ferrocene-Modified Nanoscale Covalent Organic Frameworks for Ferroptosis-Based Sonodynamic Therapy Inhibit Breast Cancer and Its Bone Metastasis

## TL;DR

A new nanomedicine uses ultrasound to trigger cell death and immune response, effectively treating breast cancer and preventing bone metastasis.

## Contribution

A sonodynamic nanoplatform combining ferroptosis and immunomodulation to inhibit breast cancer and bone metastasis.

## Key findings

- mCOFs generated ROS and •OH radicals under ultrasound, inducing apoptosis and ferroptosis in breast cancer cells.
- In mouse models, mCOFs inhibited primary tumor growth and reduced bone metastasis after ultrasound exposure.
- The treatment reprogrammed the immunosuppressive tumor microenvironment.

## Abstract

Breast cancer continues to be a marked risk to women’s health worldwide. In particular, bone metastasis stands as one of the leading causes of death among breast cancer patients. In recent years, therapies that reprogram the tumor’s immunosuppressive microenvironment have emerged as promising antimetastatic strategies. In this study, we developed a sonodynamic nanoplatform that simultaneously eradicates primary breast tumors via ferroptosis and apoptosis and blocks their spread to bone tissues. Ferrocene-grafted nanoconfined covalent organic frameworks (mCOFs) were synthesized by condensing aminoferrocene with micrometer-sized COFs, yielding a multifunctional agent capable of amplifying reactive oxygen species (ROS) production. Following ultrasound treatment, the mCOFs generated abundant ROS, while the ferrocene moieties catalyzed the Fenton-like conversion of endogenous H2O2 into cytotoxic •OH radicals. In vitro, ultrasound-activated mCOFs concurrently induced apoptosis and ferroptosis in breast cancer cells and triggered the robust release of immunogenic factors. In orthotopic mouse models, intravenously administered mCOFs preferentially accumulated in tumors; upon ultrasound exposure, these mCOFs markedly inhibited the growth of primary tumors, reprogrammed the immunosuppressive tumor microenvironment, and effectively reduced bone metastasis. This study proposes a versatile nanomedicine-based strategy that integrates sonodynamic therapy with immunomodulation to control breast cancer progression and bone metastasis, offering a broad approach for reducing metastatic disease.