Bian Xintong, Fan Ningke, Li Meng, Han Daobin, Li Jia, Fan Lu, Li Xinyu, Kong Liangsheng, Tang Hua, Ding Shijia, Song Fangzhou, Li Siqiao, Cheng Wei
The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China.
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China.
ACS Nano. 2023 Mar 14;17(5):4896-4912. doi: 10.1021/acsnano.2c11922. Epub 2023 Feb 22.
Persisting and excessive endoplasmic reticulum stress (ERS) can evoke rapid cell apoptosis. Therapeutic interference of ERS signaling holds enormous potential for cancer nanotherapy. Herein, a hepatocellular carcinoma (HCC) cell-derived ER vesicle (ERV) encapsulating siGRP94, denoted as ER-horse, has been developed for precise HCC nanotherapy. Briefly, ER-horse, like the Trojan horse, was recognized via homotypic camouflage, imitated the physiological function of ER, and exogenously opened the Ca channel. Consequently, the mandatory pouring-in of extracellular Ca triggered the aggravated stress cascade (ERS and oxidative stress) and apoptosis pathway with the inhibition of unfolded protein response by siGRP94. Collectively, our findings provide a paradigm for potent HCC nanotherapy via ERS signaling interference and exploring therapeutic interference of physiological signal transduction pathways for precision cancer therapy.
持续且过度的内质网应激（ERS）可引发快速的细胞凋亡。ERS信号的治疗性干预在癌症纳米治疗中具有巨大潜力。在此，一种包裹siGRP94的肝癌（HCC）细胞源性内质网囊泡（ERV），被命名为ER-horse，已被开发用于精准的HCC纳米治疗。简而言之，ER-horse就像特洛伊木马一样，通过同型伪装被识别，模仿内质网的生理功能，并外源打开钙通道。因此，细胞外钙的强制涌入通过siGRP94抑制未折叠蛋白反应，触发了加剧的应激级联反应（ERS和氧化应激）以及凋亡途径。总的来说，我们的研究结果为通过ERS信号干扰进行有效的HCC纳米治疗以及探索生理信号转导途径的治疗性干扰以实现精准癌症治疗提供了一个范例。
