Peptides-functionalized gold nanostars enhanced degradation of PD-L1 for improved prostate cancer immunotherapy

Abstract

Blockage of the interaction between programmed death receptor-1 (PD-1) and programmed death ligand-1 (PD-L1) can restore T-cell activity and enhance antitumor immunity. PD-1/PD-L1 pathway inhibitors have promising applications in the treatment of advanced prostate cancer (PCa). We successfully developed a peptides-functionalized gold nanoconstruct (P-AuNS) consisted of PD-L1-binding peptide (PD-L1pep, P) and gold nanostar (AuNS), which could bind to cell-surface PD-L1 specifically and deliver PD-L1 into PCa cells with high efficiency. In PCa cells, P-AuNS can efficiently degrade PD-L1 in a lysosomal-dependent manner. In the co-culture system of Jurkat cells and DU145 cells, P-AuNS restored the proliferative capacity and interferon-gamma (IFN-γ) secretion level of Jurkat cells inhibited by co-cultured DU145 cells, indicating that P-AuNS effectively hampered the interaction between PD-1 and PD-L1. In addition, in PCa-bearing mice, P-AuNS can effectively inhibit tumor growth and down-regulate PD-L1 protein levels, and in vivo experimental results show that P-AuNS has no systemic toxicity. P-AuNS block the interaction between PD-1 and PD-L1 by efficiently degrading PD-L1, thus restoring the antitumor activity of T cells and inhibiting tumor progression of PCa. In all, P-AuNS has great promise as a potential immunotherapy strategy in the treatment of advanced PCa and even other solid tumors.