构建一种肿瘤微环境（TME）响应的纳米平台NG@Fe₃O₄-PFH@CM，并探索其通过诱导铁死亡激活免疫，协同增效高强度聚焦超声（HIFU）消融治疗三阴乳腺癌（TNBC）及抑制转移的效果。

以谷胱甘肽/pH双响应性纳米凝胶为骨架，负载铁离子四氧化三铁与相变剂全氟己烷，并包覆癌细胞膜，构建响应性纳米平台NG@Fe₃O₄-PFH@CM。系统表征其理化性质与HIFU触发的声学相变行为。通过体外细胞实验与4T1乳腺癌移植瘤及转移瘤模型评价纳米平台对于HIFU增敏超声成像、生物安全、肿瘤富集、诱导铁死亡、免疫激活以及协同HIFU抑制肿瘤生长和转移的效能。

体外实验证实，该纳米平台具有良好的生物安全性、肿瘤富集能力及TME响应性药物释放特性。其在TME中释放的四氧化三铁通过芬顿反应产生大量活性氧，引发强烈的脂质过氧化，诱发铁死亡。HIFU联合NG@Fe₃O₄-PFH@CM能有效诱导细胞铁死亡并显著促进树突状细胞（DCs）成熟[（29.1±0.9）%]，较Saline对照组提升近1倍（t=21.13，P＜0.0001）。体内实验研究表明，HIFU促进的相变，显著增强了肿瘤部位的超声造影显像（NG@Fe₃O₄-PFH@CM组HIFU前后成像灰度变化：t=23.04，P＜0.0001），且由于肿瘤内DCs成熟度的显著提升[（38.5±0.8）%，为Saline对照组的2.2倍（t=36.59，P＜0.0001）]，以及后续的免疫激活，联合治疗方案取得了高达86.1%的肿瘤抑制率，有效抑制了肺转移（抑制率90.0%）；与其他对照组比较，差异有统计学意义（肿瘤抑制率：F=45.63，P＜0.0001；肺转移抑制率：F=92.96，P＜0.0001）。

本研究成功构建了一种具有TME响应释药的功能纳米平台，既能通过相变增强超声显影监控治疗，又能有效增强肿瘤铁死亡、激活细胞免疫，从而显著抑制肿瘤的增殖和远处转移，为HIFU增效研究提供新的策略。

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.