Hyaluronic acid-decorated MOF nanoplatform loaded with berbamine elicits immunogenic ferroptosis through a sonodynamic/chemodynamic/chemotherapy synergy in triple-negative breast cancer.

Abstract

Chemoresistance, inadequate tumor targeting, and severe systemic toxicity remain key barriers to effective breast cancer treatment. Ferroptosis-inducing strategies have emerged as a promising therapeutic avenue, yet their efficacy is frequently compromised by the intrinsic antioxidant defense system and insufficient immune activation within the tumor microenvironment (TME). Herein, a hyaluronic acid (HA)-functionalized, berbamine (BBM)-loaded iron-based metal-organic framework (MOF) nanoplatform (HA-FeTCPP@BBM, HAFTB) was engineered. This nanosystem executes a "three-in-one" synergistic strategy that coordinates FeTCPP-mediated sonodynamic therapy (SDT), iron-dependent chemodynamic therapy (CDT), and BBM-mediated chemotherapy and ferroptosis sensitization, while HA functionalization facilitates tumor-oriented delivery to enhance the induction of ferroptosis-associated immunogenic cell death in triple-negative breast cancer (TNBC). Upon ultrasound (US) exposure, the HAFTB scaffold functions simultaneously as a sonosensitizer and an iron source. Ultrasound activation initiates sonodynamic reactions and enhances Fenton-like catalytic activity, substantially boosting reactive oxygen species (ROS) generation. Moreover, the localized release of BBM contributes to glutathione peroxidase 4 (GPX4) suppression and weakens the cellular antioxidant defense system, thereby sensitizing tumor cells to ferroptotic stress. This tripartite oxidative stress results in extensive lipid peroxidation and robust ferroptotic cell death. Abundant damage-associated molecular patterns (DAMPs) are concurrently released, supporting the occurrence of ferroptosis-associated immunogenic responses and subsequent immune activation. In an orthotopic TNBC mouse model, HAFTB integrated with SDT achieves pronounced tumor suppression with low systemic toxicity, while transcriptomic profiling supports the involvement of ferroptosis- and oxidative stress-related pathways. Overall, the principal advance of this cascade nanoplatform lies in the coordinated integration of FeTCPP-mediated SDT, iron-dependent CDT, and BBM-associated ferroptosis sensitization within an HA-assisted MOF delivery system, providing a promising therapeutic strategy for TNBC.