通过阻断表面程序性死亡配体1（PD-L1）和程序性细胞死亡蛋白1（PD-1）相互作用的检查点抑制剂抗体疗法在癌症免疫治疗中具有广阔的前景。然而，许多患者的反应仍然不能令人满意，怀疑与位于其他细胞区室中的 PD-L1 有关，而抗体无法进入细胞内区室。在此，我们鉴定了一种具有双重作用的 PD-L1 靶向 DNA 适体 (PA9-1)，包括拮抗剂和依赖于 PD-L1 内化的递送剂。我们设计了靶向PD-L1的拮抗适体-ASO递送系统（PA9-1-ASO），该系统具有涉及阻断和沉默机制相结合的协同抑制PD-L1活性。该嵌合体不仅阻断 PD-L1/PD-1，而且还实现了缀合 ASO 的靶向递送，以减少表面 PD-L1 和总 PD-L1 表达。与单一阻断相比，这种具有双重抑制功能的嵌合体可以协同抑制PD-L1，从而放大免疫治疗效果，为免疫治疗提供了一种有前途的协同策略。版权所有©2023 Elsevier Ltd.保留所有权利。

Checkpoint inhibitor antibody therapy by blocking the interaction of surface programmed death-ligand 1(PD-L1) and programmed cell death protein 1(PD-1) has promising advantages in cancer immunotherapy. However, the response of many patients remains unsatisfactorily, suspected to be relevant to PD-L1 located in other cellular compartments and antibodies do not have access to the intracellular compartments. Herein, we identify a PD-L1-targeting DNA aptamer (PA9-1) with dual roles, including an antagonist and a delivery agent dependent on PD-L1 internalization. And we design the PD-L1-targeting antagonistic aptamer-ASO delivery system (PA9-1-ASO), with synergistic inhibitory PD-L1 activity involving the combination of blockade and silencing mechanisms. This chimera not only blocks PD-L1/PD-1 but also achieves targeted delivery of the conjugated ASO to reduce both surface PD-L1 and total PD-L1 expression. Compared with the single blockade, this chimera with the dual inhibitory function synergistically inhibits PD-L1 to amplify immunotherapeutic efficacy, providing a promising synergistic strategy for immunotherapy.Copyright © 2023 Elsevier Ltd. All rights reserved.