肝细胞癌（HCC）是全球范围内发病率和死亡率均居前列的恶性肿瘤，具有起病隐匿、进展迅速和复发率高等特点，导致多数患者在确诊时已处于中晚期，错过最佳治疗时机。虽然目前治疗HCC的方法包括手术切除、肝移植、放化疗、分子靶向治疗和免疫治疗等，但由于肿瘤异质性强和微环境复杂，现有治疗手段常面临疗效差、毒副作用大和耐药性强等问题。因此，开发具有良好靶向性和高治疗效率的新型策略，对提高HCC治疗水平具有重要意义。

铁死亡是一种依赖铁离子并由脂质过氧化物积累引发的程序性细胞死亡方式。肝脏作为机体的主要储存器官，富含铁储存蛋白和铁转运蛋白，因此对铁死亡机制尤为敏感。在HCC治疗中，诱导铁死亡可以有效克服传统治疗手段的耐药问题。已有研究发现，诱导细胞内活性氧（ROS）积累、干扰谷胱甘肽（GSH）代谢、抑制GPX4活性等均可激发铁死亡过程。然而，如何在保证生物安全性的前提下高效激活铁死亡通路，仍是当前HCC治疗的难点之一。

本研究设计并构建了一种整合声动力治疗（SDT）、化学动力学治疗（CDT）及气体治疗的HCC靶向仿生纳米平台。该平台以双金属氧化物FeMoO4纳米颗粒为核心，利用其类芬顿活性实现CDT功能，通过催化肿瘤内H2O2产生活性氧增强氧化应激，同时为CO供体CORM-401提供载体空间。CORM-401作为一种ROS响应性CO释放分子，在超声介导下局部释放CO，通过抑制线粒体电子传递链复合物IV活性诱导线粒体功能紊乱，进一步提升ROS水平，从而协同诱导铁死亡。

为进一步提升体内稳定性与肿瘤靶向性，本研究以来源于RAW264.7细胞的巨噬细胞膜为仿生包裹材料，并修饰SP94肽，构建了具有免疫逃逸能力和肝癌主动靶向能力的功能化纳米平台。体外实验显示，该纳米平台可在超声作用下高效产生活性氧、释放CO并消耗细胞内GSH，诱导肝癌细胞铁死亡。免疫蛋白印迹结果验证了GPX4关键蛋白表达的显著下调，实时定量PCR也进一步印证了相关基因的转录水平变化。体内实验证实，该平台在Hepa 1-6荷瘤小鼠模型中具有显著的肿瘤生长抑制效果，并未引发明显系统毒性，具有良好的生物安全性。

本研究提出了一种融合多种治疗机制的协同策略，通过声响应控制下的ROS与CO释放，靶向激活HCC细胞内的铁死亡反应，展现出优异的治疗效果和临床转化潜力，为HCC的精准治疗提供了新的思路。

老Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancies worldwide. Due to its insidious onset, rapid progression, and high recurrence rate, most patients are diagnosed at an advanced stage, missing the optimal window for treatment. Although current treatment options for HCC include surgical resection, liver transplantation, chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy, these approaches are often limited by poor efficacy, severe side effects, and drug resistance caused by tumor heterogeneity and complex microenvironments. Therefore, the development of novel therapeutic strategies with high targeting ability and treatment efficiency is of great significance for improving HCC outcomes. Ferroptosis is a form of programmed cell death characterized by iron dependency and lipid peroxidation. As the primary iron storage organ in the body, the liver is highly sensitive to ferroptotic mechanisms. Inducing ferroptosis has emerged as an effective strategy to overcome resistance in traditional HCC therapies. Previous studies have shown that intracellular accumulation of reactive oxygen species (ROS), depletion of glutathione (GSH), and inhibition of glutathione peroxidase 4 (GPX4) activity can all trigger ferroptosis. However, efficiently activating the ferroptotic pathway while ensuring biosafety remains a major challenge in current HCC treatment. In this study, we developed a biomimetic nanoplatform integrating sonodynamic therapy (SDT), chemodynamic therapy (CDT), and gas therapy for targeted treatment of HCC. The platform is centered on bimetallic oxide FeMoO4 nanoparticles, which exhibit Fenton-like catalytic activity to convert endogenous H2O2 into ROS, thereby enhancing oxidative stress for CDT. Simultaneously, FeMoO4 serves as a nanocarrier for the CO-releasing molecule CORM-401. As a ROS-responsive CO donor, CORM-401 releases CO under ultrasound irradiation, which inhibits the activity of mitochondrial electron transport chain complex IV, leading to mitochondrial dysfunction and further ROS generation, ultimately promoting ferroptosis in a synergistic manner. To enhance in vivo stability and tumor targeting ability, the nanoplatform was further cloaked with macrophage membranes derived from RAW264.7 cells and modified with SP94 peptides, thus endowing the system with immune evasion capability and active targeting toward liver cancer cells. In vitro experiments demonstrated that the nanoplatform could efficiently generate ROS, release CO, deplete intracellular GSH, and induce ferroptosis in liver cancer cells under ultrasound stimulation. In vivo studies using a Hepa 1-6 tumor-bearing mouse model revealed that the nanoplatform exhibited potent antitumor effects without causing noticeable systemic toxicity, indicating good biocompatibility. In conclusion, this study proposes a multi-mechanism therapeutic strategy that combines ROS and CO release under ultrasound control to activate ferroptosis in HCC cells in a targeted and efficient manner. This platform demonstrates excellent therapeutic performance and clinical translational potential, offering a new approach for precise treatment of HCC.