PDF(Pubmed)
Abstract：
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway has been a promising target for anticancer immunity, but rationally activating and enhancing this pathway in tumour cells is critical. Herein, a glutathione sensitive ZnFe2O4-based nanosystem is developed to programmatically initiate and enhance the STING signalling pathway in tumour cells. The prepared ZnFe2O4 nanoparticles were coated with cancer cell membrane (CCM), which enabled the nanosystem target tumour cells. In tumour cells, ZnFe2O4 nanoparticles could be disintegrated by responding to high level glutathione, and the released Fe3+ generated reactive oxygen species to induce the DNA leakage into the cytoplasm to stimulate cGAS. Then Zn2+ promoted cGAS-DNA phase separation to intensify the cGAS enzymatic activity. In addition, the low dose encapsulation of paclitaxel (PTX) acting as an antimitotic agent (ZnFe2O4-PTX@CCM) ensured the sustained activation of cGAS/STING pathway. The in vitro and in vivo results confirmed that ZnFe2O4-PTX@CCM elevated the cGAS/STING activity, promoted dendritic cell maturation, increased cytotoxic T lymphocyte and natural killer cells infiltration, eventually inhibiting the tumour progress and postoperative recurrence. This study provided feasible references on constructing STING activation nanosystem for tumour immunotherapy.
摘要：
环磷酸鸟苷-磷酸腺苷合成酶（cGAS）/干扰素基因刺激因子（STING）信号通路一直是抗癌免疫的一个有希望的目标，但是合理地激活和增强肿瘤细胞中的这一途径至关重要。在这里，开发了谷胱甘肽敏感的ZnFe2O4基纳米系统，以编程方式启动和增强肿瘤细胞中的STING信号通路。将制备的ZnFe2O4纳米粒子包覆癌细胞膜(CCM),这使得纳米系统能够靶向肿瘤细胞。在肿瘤细胞中，ZnFe2O4纳米颗粒可以通过响应高水平的谷胱甘肽而分解，释放的Fe3+产生活性氧，诱导DNA漏入细胞质，刺激cGAS。然后Zn2促进cGAS-DNA相分离以增强cGAS酶活性。此外,作为抗有丝分裂剂的紫杉醇（PTX）的低剂量封装（ZnFe2O4-PTX@CCM）确保了cGAS/STING途径的持续激活。体外和体内结果证实，ZnFe2O4-PTX@CCM提高了cGAS/STING的活性，促进树突状细胞成熟，细胞毒性T淋巴细胞和自然杀伤细胞浸润增加，最终抑制肿瘤进展和术后复发。本研究为构建肿瘤免疫治疗的STING活化纳米系统提供了可行的参考。
