Key Laboratory for Advanced Materials, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China.
ACS Appl Bio Mater. 2021 Jul 19;4(7):5735-5741. doi: 10.1021/acsabm.1c00507. Epub 2021 Jul 2.
Reactivation of T-cell immunity by blocking the PD-1/PD-L1 immune checkpoint has been considered a promising strategy for cancer treatment. However, the recognition of PD-L1 by antibodies is usually suppressed due to the N-linked glycosylation of PD-L1. In this study, we present an effective PD-L1-blocking strategy based on a sialidase-conjugated "NanoNiche" to improve the antitumor effect via T-cell reactivation. Molecularly imprinted by PD-L1 N-glycans, NanoNiche can specifically recognize glycosylated PD-L1 on the tumor cell surface, thereby resulting in more efficient PD-L1 blockade. Moreover, sialidase modified on the surface of NanoNiche can selectively strip sialoglycans from tumor cells, enhancing immune cell infiltration. In vitro studies confirmed that NanoNiche can specifically bind with PD-L1 while also desialylate the tumor cell surface. The proliferation of PD-L1-positive MDA-MB-231 human breast cancer cells under T-cell killing was significantly inhibited after NanoNiche treatment. In vivo experiments in solid tumors show enhanced therapeutic efficacy. Thus, the NanoNiche-sialidase conjugate represents a promising approach for immune checkpoint blockade therapy.
阻断 PD-1/PD-L1 免疫检查点的 T 细胞免疫激活被认为是癌症治疗的一种有前途的策略。然而，由于 PD-L1 的 N-连接糖基化，抗体对 PD-L1 的识别通常受到抑制。在本研究中，我们提出了一种基于唾液酸酶偶联的“纳米巢”的有效 PD-L1 阻断策略，通过 T 细胞再激活来提高抗肿瘤效果。通过 PD-L1 N-糖基的分子印迹，NanoNiche 可以特异性识别肿瘤细胞膜上糖基化的 PD-L1，从而实现更有效的 PD-L1 阻断。此外，表面修饰的唾液酸酶可以从肿瘤细胞上选择性地去除唾液酸糖，增强免疫细胞浸润。体外研究证实，NanoNiche 可以特异性地与 PD-L1 结合，同时也可以使肿瘤细胞表面去唾液酸化。在 NanoNiche 处理后，PD-L1 阳性的 MDA-MB-231 人乳腺癌细胞在 T 细胞杀伤下的增殖明显受到抑制。在实体瘤的体内实验中显示出增强的治疗效果。因此，NanoNiche-唾液酸酶偶联物代表了一种有前途的免疫检查点阻断治疗方法。
