Deep Downregulation of PD-L1 by Caged Peptide-Conjugated AIEgen/miR-140 Nanoparticles for Enhanced Immunotherapy.

Downregulating programmed cell death ligand 1(PD-L1) protein levels in tumor cells is an effective way to achieve immune system activation for oncology treatment, but current strategies are inadequate. Here, we design a caged peptide-AIEgen probe (GCP) to self-assemble with miR-140 forming GCP/miR-140 nanoparticles. After entering tumor cells, GCP/miR-140 disassembles in the presence of Cathepsin B (CB) and releases caged GO203 peptide, miR-140 and PyTPA. Peptide decages in the highly reductive intracellular environment and binds to mucin 1 (MUC1), thereby downregulating the expression of PD-L1. Meanwhile, miR-140 reduces PD-L1 expression by targeting downregulation of PD-L1 mRNA. Under the action of PyTPA-mediated photodynamic therapy (PDT), tumor-associated antigens are released, triggering immune cell attack on tumor cells. This multiple mechanism-based strategy of deeply downregulating PD-L1 in tumor cells activates the immune system and thus achieves effective immunotherapy.