Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, P. R. China.
Laboratory Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, P. R. China.
Adv Mater. 2023 Sep;35(35):e2302961. doi: 10.1002/adma.202302961. Epub 2023 Jul 14.
Pyroptosis, a distinct paradigm of programmed cell death, is an efficient strategy against cancer by overcoming resistance to apoptosis. In this study, LaCoO (LCO) lanthanide-based nanocrystals with multienzyme characteristics are rationally designed and engineered to trigger the generation of cytotoxic reactive oxygen species (ROS) and the release of lanthanum ions, ultimately inducing lung cancer cell pyroptosis. The peroxidase- and oxidase-mimicking activities of LCO nanocrystals endow LCO with ROS production capacity in tumor tissues with an acidic pH and high hydrogen peroxide content. Concurrently, the LCO nanoenzyme exhibits catalase- and glutathione peroxidase-like activities, reversing the hypoxic microenvironment, destroying the activated antioxidant system of tumor cells, and amplifying the sensitivity of tumor cells to ROS. The use of ultrasound further accelerates the enzymatic kinetic rate. Most importantly, the La ions released by LCO robustly destroy the lysosomal membrane, finally inducing canonical pyroptotic cell death, together with ROS. LCO-nanocrystal-triggered programmed cell pyroptosis amplifies the therapeutic effects both in vitro and in vivo, effectively restraining lung cancer growth and metastasis. This study paves a new avenue for the efficient treatment of lung cancer and metastasis through US-enhanced lanthanum-based nanoenzyme platforms and pyroptotic cell death.
细胞焦亡是一种独特的程序性细胞死亡方式，它通过克服细胞凋亡抵抗来有效对抗癌症。在本研究中，我们设计并构建了具有多酶特性的镧钴氧化物（LCO）纳米晶作为一种合理的策略来触发细胞毒性活性氧（ROS）的产生和镧离子的释放，最终诱导肺癌细胞发生细胞焦亡。LCO 纳米晶具有过氧化物酶和氧化酶模拟活性，使其在酸性 pH 值和高过氧化氢含量的肿瘤组织中具有产生 ROS 的能力。同时，LCO 纳米酶表现出过氧化氢酶和谷胱甘肽过氧化物酶样的活性，逆转缺氧微环境，破坏肿瘤细胞的激活抗氧化系统，并放大肿瘤细胞对 ROS 的敏感性。超声的使用进一步加速了酶的动力学速率。最重要的是，LCO 释放的 La 离子强烈破坏溶酶体膜，最终诱导经典的细胞焦亡死亡，与 ROS 一起作用。LCO 纳米晶触发的程序性细胞焦亡在体外和体内均增强了治疗效果，有效抑制了肺癌的生长和转移。本研究为通过超声增强的基于镧的纳米酶平台和细胞焦亡死亡来有效治疗肺癌和转移开辟了新途径。
