Abstract：
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.
摘要：
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）的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有希望的优势。然而,许多患者的反应仍然不令人满意，怀疑与位于其他细胞区室的PD-L1相关，抗体无法进入细胞内区室。在这里，我们确定了具有双重作用的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。并设计了PD-L1靶向拮抗适体-ASO传递系统(PA9-1-ASO),具有协同抑制性PD-L1活性，涉及阻断和沉默机制的组合。该嵌合体不仅阻断PD-L1/PD-1,而且实现缀合的ASO的靶向递送以减少表面PD-L1和总PD-L1表达两者。与单一封锁相比，这种具有双重抑制功能的嵌合体协同抑制PD-L1增强免疫治疗功效，为免疫治疗提供了一种有前途的协同策略。
