Selective Degradation of PD-L1 in Cancer Cells by Enzyme-Instructed Self-Assembly

Here, a novel strategy to selectively degrade membrane proteins of programmed cell death-ligand 1 (PD-L1) in cancer cells is reported. 4T1 cells show high levels of extracellular alkaline phosphatase (ALP) and membrane proteins of PD-L1. Therefore, peptide derivatives capable of responding to ALP and binding to PD-L1 are designed. Enzyme-instructed self-assembly (EISA) by ALP and surface-induced self-assembly by PD-L1 of Comp. 3 leads to the selective formation of nanomaterials around PD-L1 on the cell membrane, which is similar to attaching a hydrophobic label to the surface of PD-L1 to simulate its partial denaturation state. When taken up by cells, PD-L1 could be further degraded by the proteasome pathway in the cytoplasm. This process does not occur in the normal cell line, LO2 cells, which express relatively low levels of ALP. In addition to concentration and time dependence, the selective knock-out of PD-L1 by the strategy is reversible by simply removing Comp. 3. In vivo studies reveal that Comp. 3 inhibits tumor growth in a tumor-bearing mouse model. The study offers a novel platform for the precise degradation of membrane proteins using EISA, which might ultimately lead to the development of novel nanomedicines to treat diseases.