Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, characterized by invasiveness, local lymph node metastasis, and poor prognosis. Traditional treatment and medications have limitations, making the specific inhibition of OSCC growth, invasion, and metastasis a challenge. The tumor microenvironment exhibits mildly acidity and high concentrations of H2O2, and its exploitation for cancer treatment has been widely researched across various cancers, but research in the oral cancer field is relatively limited. In this study, by loading ultra-small Prussian blue nanoparticles (USPBNPs) into mesoporous calcium–silicate nanoparticles (MCSNs), we developed an acid-responsive iron-based nanocomposite, USPBNPs@MCSNs (UPM), for the OSCC treatment. UPM demonstrated excellent dual enzyme activities, generating toxic ·OH in a mildly acidic environment, effectively killing OSCC cells and producing O2 in a neutral environment to alleviate tissue hypoxia. The results showed that UPM could effectively inhibit the proliferation, migration, and invasion of OSCC cells, as well as the growth of mice solid tumors, without obvious systemic toxicity. The mechanisms may involve UPM inducing ferroptosis of OSCC cells by downregulating the xCT/GPX4/glutathione (GSH) axis, characterized by intracellular iron accumulation, reactive oxygen species accumulation, GSH depletion, lipid peroxidation, and abnormal changes in mitochondrial morphology. Therefore, this study provides empirical support for ferroptosis as an emerging therapeutic target for OSCC and offers a valuable insight for future OSCC treatment.

中文翻译：

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用于治疗口腔鳞癌的酸响应性铁基纳米复合材料

口腔鳞状细胞癌（OSCC）是最常见的口腔癌类型，具有侵袭性、局部淋巴结转移、预后差等特点。传统的治疗和药物具有局限性，使得特异性抑制口腔鳞癌的生长、侵袭和转移成为一个挑战。肿瘤微环境呈现弱酸性和高浓度 H2氧2，其在癌症治疗中的应用已在各种癌症中得到广泛研究，但口腔癌领域的研究相对有限。在这项研究中，通过将超小普鲁士蓝纳米粒子（USPBNPs）负载到介孔硅酸钙纳米粒子（MCSNs）中，我们开发了一种酸响应性铁基纳米复合材料USPBNPs@MCSNs（UPM），用于OSCC治疗。 UPM表现出优异的双酶活性，在弱酸性环境下产生有毒·OH，有效杀死OSCC细胞并产生O2处于中性环境，缓解组织缺氧。结果表明，UPM能有效抑制OSCC细胞的增殖、迁移和侵袭，以及小鼠实体瘤的生长，且无明显的全身毒性。其机制可能涉及 UPM 通过下调 xCT/GPX4/谷胱甘肽 (GSH) 轴诱导 OSCC 细胞铁死亡，其特征是细胞内铁积累、活性氧积累、GSH 耗竭、脂质过氧化和线粒体形态异常变化。因此，本研究为铁死亡作为 OSCC 的新兴治疗靶点提供了实证支持，并为未来 OSCC 的治疗提供了宝贵的见解。