Fan Mengke, Yang Pan, Huo Linlin, Bao Jianfeng, Tan Mingya, Zeng Jie, Zhu Shiqi, Liu Meiling, Zhao Jiayi, Miao Wenjun, Zhao Zhenghuan
College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
Functional Magnetic Resonance and Molecular Imaging Key Laboratory of Henan Province, Department of Magnetic Resonance Imaging, First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450001, China.
Acta Biomater. 2025 Mar 1;194:385-395. doi: 10.1016/j.actbio.2025.01.044. Epub 2025 Jan 25.
Cuproptosis is a newly discovered mode of cell death, which is caused by excess copper and results in cell death via the mitochondrial pathway. However, the complex tumor microenvironment (TME) is characterized by many factors, including high levels of glutathione and lack O, limit the application of traditional cuproptosis agents in antitumor therapy. Herein, we report a hyaluronic acid modified copper-manganese composite nanomedicine (CMCNs@HA) to remodel the TME and facilitate efficient cuproptosis in tumor. The integration of CuO and MnO into CMCNs@HA endows this nanoplatform to generate O and deplete GSH in tumor site, ensuring the environment is beneficial to the cuproptosis of tumor. The glutathione (GSH) depletion process is accompanied by the release of Mn ions. The released Mn ions improve the cuproptosis through efficient chemodynamic therapy and initiate immune response via activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which significantly suppresses tumor growth and inhibits tumor metastases. In addition, the Mn ions release process enables this nanoplatform to work as activable T contrast agent to achieve accurate tumor diagnosis. This functionally complementary composite metal nanomaterial may provide effective ideas regarding the application of cuproptosis in designing tumor therapeutic regimens. STATEMENT OF SIGNIFICANCE: Cuproptosis in combination with cGAS-STING offers significant potential for tumor treatment. Here, we constructed TME responsive copper-manganese composite nanomaterials (CMCNs@HA) to augment tumor cuproptosis. GSH depletion, hypoxia relief, and effective chemodynamic therapy caused by CMCNs@HA facilitate the progression of cuproptosis. Besides, CMCNs@HA successfully initiate immune response via activating the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and significantly inhibits tumor metastases. Simultaneously, released Mn ions provide real-time magnetic resonance imaging (MRI) signal changes, enabling accurate tumor diagnosis and monitoring of the therapeutic process.
铜死亡是一种新发现的细胞死亡模式，由过量铜引起，并通过线粒体途径导致细胞死亡。然而，复杂的肿瘤微环境（TME）具有多种特征因素，包括高水平的谷胱甘肽和缺氧，这限制了传统铜死亡剂在抗肿瘤治疗中的应用。在此，我们报道了一种透明质酸修饰的铜锰复合纳米药物（CMCNs@HA），用于重塑肿瘤微环境并促进肿瘤细胞的有效铜死亡。将氧化铜和氧化锰整合到CMCNs@HA中，使该纳米平台能够在肿瘤部位产生氧气并消耗谷胱甘肽，确保环境有利于肿瘤细胞的铜死亡。谷胱甘肽（GSH）的消耗过程伴随着锰离子的释放。释放的锰离子通过有效的化学动力学疗法促进铜死亡，并通过激活环磷酸鸟苷-腺苷酸合酶-干扰素基因刺激因子（cGAS-STING）途径引发免疫反应，从而显著抑制肿瘤生长并抑制肿瘤转移。此外，锰离子的释放过程使该纳米平台能够作为可激活的T1对比剂实现准确的肿瘤诊断。这种功能互补的复合金属纳米材料可能为铜死亡在设计肿瘤治疗方案中的应用提供有效的思路。重要意义声明：铜死亡与cGAS-STING联合应用在肿瘤治疗方面具有巨大潜力。在此，我们构建了肿瘤微环境响应性铜锰复合纳米材料（CMCNs@HA）以增强肿瘤细胞的铜死亡。CMCNs@HA引起的谷胱甘肽消耗、缺氧缓解和有效的化学动力学疗法促进了铜死亡的进程。此外，CMCNs@HA通过激活环磷酸鸟苷-腺苷酸合酶-干扰素基因途径成功引发免疫反应，并显著抑制肿瘤转移。同时，释放的锰离子提供实时磁共振成像（MRI）信号变化，实现准确的肿瘤诊断和治疗过程监测。
