Site-specific nanoswitch circumventing immune resistance via activating TLR and inhibiting PD-L1/PD-1 axis.
Site-specific nanoswitch circumventing immune resistance via activating TLR and inhibiting PD-L1/PD-1 axis.
复制标题
DOI：
10.1016/j.jconrel.2023.07.048
复制
发表时间：
2023-07
期刊：
影响因子：
--
通讯作者：
Yanyun Hao;Hui Li;Xiaoyan Ge;Yang Liu;Jialin Yin;Xia Li;Yutong Liu;Hongfei Chen;Lingling Huang;Jing Zou;Shiying Zhang;Hao Wu;Zhiyue Zhang
中科院分区：
文献类型：
--
作者：
Yanyun Hao;Hui Li;Xiaoyan Ge;Yang Liu;Jialin Yin;Xia Li;Yutong Liu;Hongfei Chen;Lingling Huang;Jing Zou;Shiying Zhang;Hao Wu;Zhiyue Zhang
免疫疗法从根本上改变了癌症治疗;然而，其有效性在临床上受到肿瘤内T淋巴细胞浸润不足和T淋巴细胞引发失败的阻碍。此外，诱导癌症特异性免疫反应，同时保留正常细胞仍然具有挑战性。在此，我们开发了一种可氧化还原激活的聚合物纳米开关（c-N@IM/JQ），其在循环中保持“关闭”状态，但在进入肿瘤后迅速打开。Toll样受体（TLR）7/8激动剂（咪唑并喹啉，IMQ）和溴结构域和末端外抑制剂（JQ 1）用氧化还原可切割接头（关闭）锁定在c-N@IM/JQ中。在全身给药后，具有c-RGD肽修饰的c-N@IM/JQ优先在肿瘤部位积累，并响应于高谷胱甘肽水平以释放天然IMQ用于完全动员T淋巴细胞军团，以及释放JQ 1用于去除肿瘤细胞上的程序性死亡配体（PD-L）-1保护（开启）。这些增强的T淋巴细胞军队很容易接近这些去保护的肿瘤细胞，恢复对肿瘤的免疫反应。
Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained ‘off’ status in circulation but rapidly switched ‘on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration, c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors.