封锁
癌症研究
免疫疗法
癌症免疫疗法
免疫检查点
免疫系统
PD-L1
癌症
免疫抑制
T细胞
医学
免疫学
受体
内科学
作者
LU Hai-feng,Peixin Guan,Shuxin Xu,Yanjie Han,Zhen Liu
出处
期刊:ACS Nano
[American Chemical Society]
日期:2024-08-13
标识
DOI:10.1021/acsnano.4c07416
摘要
Immune checkpoint blockade therapy has achieved important clinical advances in several types of tumors, particularly via targeting the PD-1/PD-L1 axis. However, existing therapeutic strategies that suppress the PD-1/PD-L1 signal pathway usually experience low treatment efficacy and the risk of causing autoimmune diseases. Herein, we report a cancer cell–targeted molecularly imprinted lysosomal nanodegrader (MILND) for boosting immune checkpoint blockade therapy against tumors. The MILND, imprinted with the N-terminal epitope of PD-L1 as an imprinting template, could specifically target the PD-L1 on tumor cells to promote cellular uptake. This process further induces the transport of PD-L1 into lysosomes for degradation, ultimately resulting in the downregulation of PD-L1 expression levels on tumor cells. As a result, a T cell–mediated immune response in the body was activated via the blockade of the PD-1/PD-L1 signaling pathway, which triggered a durable antitumor efficacy. In vivo experiments demonstrated that the MILND could effectively accumulate in tumor sites and exhibit strong tumor growth suppression efficacy in a xenograft tumor model without obvious side effects. Therefore, the MILND provides not only a promising strategy for boosting cancer immunotherapy but also insights for developing molecular imprinting–empowered nanomedicines.
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