To construct a novel tumor microenvironment (TME)-responsive nanoplatform, NG@Fe₃O₄-PFH@CM, and to explore its potential to synergize with high-intensity focused ultrasound (HIFU) ablation therapy for triple-negative breast cancer (TNBC) by inducing ferroptosis and activating anti-tumor immunity.

We fabricated a responsive nanoplatform (NG@Fe₃O₄-PFH@CM) using a glutathione/pH dual-responsive nanogel as the framework to encapsulate ferric ion-loaded Fe₃O₄ and the phase-change agent perfluorohexane (PFH), which was then coated with cancer cell membranes (CM). The physicochemical properties of the nanoplatform and its HIFU-triggered acoustic phase-change behavior were systematically characterized. The efficacy of the nanoplatform was evaluated in vitro and in 4T1 breast cancer orthotopic and metastasis models. Assessments included its ability to enhance HIFU-sensitized ultrasound imaging, biocompatibility, tumor accumulation, ferroptosis induction, immune activation, and its synergistic effect with HIFU on inhibiting tumor growth and metastasis.

In vitro experiments confirmed that the nanoplatform exhibited excellent biocompatibility, tumor accumulation capacity, and tumor microenvironment (TME)-responsive drug release profiles. The Fe₃O₄ released within the TME resulted in the generation of substantial reactive oxygen species (ROS) via the Fenton reaction, triggering severe lipid peroxidation and inducing ferroptosis. HIFU combined with NG@Fe₃O₄-PFH@CM effectively induced cellular ferroptosis and significantly promoted dendritic cell (DC) maturation (29.1±0.9%), nearly doubling the rate observed in the Saline group (t=21.13, P＜0.0001). In vivo studies indicated that the HIFU-triggered phase transition significantly enhanced contrast-enhanced ultrasound (CEUS) imaging at the tumor site. Driven by the marked elevation in intratumoral DC maturation (38.5±0.8%, 2.2 times that of the Saline group; t=36.59, P＜0.0001) and the consequent immune activation, the combination therapy achieved a tumor inhibition rate of 86.1% (F=45.63, P＜0.0001) and effectively suppressed lung metastasis (inhibition rate of 90.0%, F=92.96, P＜0.0001).

We have successfully constructed a functional nanoplatform with TME-responsive drug release. This platform not only enhances ultrasound imaging for treatment monitoring through phase change but also effectively boosts tumor ferroptosis and activates cellular immunity, thereby significantly inhibiting tumor proliferation and distant metastasis. This work provides a new strategy for enhancing HIFU efficacy.