通过基于 ZnFe2O4 的定制纳米系统,为肿瘤免疫疗法启动和增强 cGAS/STING 通路

Jing Yang, Yuping He, Meng Zhang, Chenglin Liang, Tongtong Li, Tianjiao Ji, Mali Zu, Xu Ma, Zhenzhong Zhang, Chun Liang, Qixu Zhang, Youbai Chen, Lin Hou
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引用次数: 0

摘要

环鸟苷单磷酸-腺苷单磷酸合成酶(cGAS)/干扰素基因刺激器(STING)信号通路一直是抗癌免疫的一个有希望的靶点,但在肿瘤细胞中合理地激活和增强这一通路至关重要。本文开发了一种谷胱甘肽敏感的 ZnFe2O4 纳米系统,可在肿瘤细胞中程序化地启动和增强 STING 信号通路。制备出的 ZnFe2O4 纳米颗粒表面包覆有癌细胞膜(CCM),从而使纳米系统能够靶向肿瘤细胞。在肿瘤细胞中,ZnFe2O4 纳米粒子可在高浓度谷胱甘肽的作用下解体,释放出的 Fe3+ 产生活性氧,诱导 DNA 泄漏到细胞质中,从而刺激 cGAS。然后,Zn2+ 促进 cGAS-DNA 相分离,从而增强 cGAS 的酶活性。此外,低剂量封装的紫杉醇(PTX)作为一种抗抑制剂(ZnFe2O4-PTX@CCM)确保了 cGAS/STING 通路的持续激活。体外和体内研究结果证实,ZnFe2O4-PTX@CCM 可提高 cGAS/STING 活性,促进树突状细胞成熟,增加细胞毒性 T 淋巴细胞和自然杀伤细胞浸润,最终抑制肿瘤进展和术后复发。这项研究为构建 STING 激活纳米系统用于肿瘤免疫治疗提供了可行的参考。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Programmed initiation and enhancement of cGAS/STING pathway for tumour immunotherapy via tailor-designed ZnFe2O4-based nanosystem

Programmed initiation and enhancement of cGAS/STING pathway for tumour immunotherapy via tailor-designed ZnFe2O4-based nanosystem

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.

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