Layered double hydroxide nanoplatform synergizes with sonodynamic therapy to induce dual activation of cuproptosis and ferroptosis for breast cancer treatment.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options and poor prognosis, creating an urgent demand for novel strategies. Sonodynamic therapy (SDT) is a promising non-invasive approach, yet its clinical translation is restricted by low efficacy of traditional sonosensitizers and single-modal limitations. In this study, we constructed a zinc‑copper‑iron-based layered double hydroxide (ZnCuFe@LDHs) nanoplatform integrating SDT with synergistic ferroptosis and cuproptosis for targeted TNBC treatment. In vitro experiments with 4 T1 cells demonstrated efficient cellular internalization and lysosomal escape of ZnCuFe@LDHs. Under ultrasound stimulation, the nanoplatform generated abundant reactive oxygen species (ROS) and released Cu2+/Fe3+ in response to the acidic tumor microenvironment (TME) and elevated intracellular glutathione (GSH). These events synergistically triggered ferroptosis by inactivating glutathione peroxidase 4 (GPX4) and accumulating lipid peroxide, while inducing cuproptosis through Cu2+ overload, mitochondrial dysfunction, tricarboxylic acid cycle disruption and lipoylated dihydrolipoamide acetyltransferase (DLAT) oligomerization. Additionally, ZnCuFe@LDHs triggered immunogenic cell death (ICD) characterized by calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release, promoting dendritic cell maturation and antitumor immunity. In vivo studies using 4 T1 subcutaneous xenograft models confirmed significant tumor growth suppression by ZnCuFe@LDH and ultrasound, with no obvious systemic toxicity. Serum biochemical analysis and histological examination of major organs validated favorable biocompatibility. Collectively, ZnCuFe@LDHs achieves potent targeted antitumor efficacy via the integration of SDT, ferroptosis, cuproptosis, andimmunogenic cell death(ICD). This quadruple-modal synergistic strategy offers a safe and translational therapeutic option for TNBC.