Dai Jun, Hu Jing-Jing, Dong Xiaoqi, Chen Biao, Dong Xiyuan, Liu Rui, Xia Fan, Lou Xiaoding
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China.
Angew Chem Int Ed Engl. 2022 Apr 25;61(18):e202117798. doi: 10.1002/anie.202117798. Epub 2022 Mar 9.
Downregulating programmed cell death ligand 1(PD-L1) protein levels in tumor cells is an effective way to achieve immune system activation for oncology treatment, but current strategies are inadequate. Here, we design a caged peptide-AIEgen probe (GCP) to self-assemble with miR-140 forming GCP/miR-140 nanoparticles. After entering tumor cells, GCP/miR-140 disassembles in the presence of Cathepsin B (CB) and releases caged GO203 peptide, miR-140 and PyTPA. Peptide decages in the highly reductive intracellular environment and binds to mucin 1 (MUC1), thereby downregulating the expression of PD-L1. Meanwhile, miR-140 reduces PD-L1 expression by targeting downregulation of PD-L1 mRNA. Under the action of PyTPA-mediated photodynamic therapy (PDT), tumor-associated antigens are released, triggering immune cell attack on tumor cells. This multiple mechanism-based strategy of deeply downregulating PD-L1 in tumor cells activates the immune system and thus achieves effective immunotherapy.
下调肿瘤细胞中程序性细胞死亡配体1（PD-L1）蛋白水平是实现肿瘤治疗免疫系统激活的有效方法，但目前的策略并不完善。在此，我们设计了一种笼形肽-聚集诱导发光探针（GCP），使其与miR-140自组装形成GCP/miR-140纳米颗粒。进入肿瘤细胞后，GCP/miR-140在组织蛋白酶B（CB）存在的情况下分解，并释放出笼形GO203肽、miR-140和PyTPA。肽在高度还原的细胞内环境中脱笼并与粘蛋白1（MUC1）结合，从而下调PD-L1的表达。同时，miR-140通过靶向下调PD-L1 mRNA来降低PD-L1表达。在PyTPA介导的光动力疗法（PDT）作用下，肿瘤相关抗原被释放，触发免疫细胞对肿瘤细胞的攻击。这种基于多种机制在肿瘤细胞中深度下调PD-L1的策略激活了免疫系统，从而实现有效的免疫治疗。
