Deep Downregulation of PD-L1 by Caged Peptide-Conjugated AIEgen/miR-140 Nanoparticles for Enhanced Immunotherapy
Jun Dai1, Jing-Jing Hu2, Xiaoqi Dong2
1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
Abstract:
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.
Insights
This study introduces a novel nanoparticle that effectively reduces programmed cell death ligand 1 (PD-L1) in cancer cells. This approach enhances the immune system
Area of Science:
- Biomedical Engineering
- Oncology
- Immunotherapy
Background:
- Downregulating programmed cell death ligand 1 (PD-L1) is crucial for activating the immune system in cancer treatment.
- Current methods for PD-L1 downregulation are insufficient for effective immunotherapy.
Purpose of the Study:
- To develop a novel nanoparticle-based strategy for enhanced PD-L1 downregulation in tumor cells.
- To investigate a multi-mechanism approach combining peptide delivery, microRNA, and photodynamic therapy for cancer immunotherapy.
Main Methods:
- Design of a caged peptide-AIEgen probe (GCP) that self-assembles with miR-140 into nanoparticles.
- Intracellular disassembly triggered by Cathepsin B (CB) to release GO203 peptide, miR-140, and PyTPA.
- MUC1-binding peptide (GO203) for PD-L1 protein downregulation and miR-140 for mRNA targeting.
- PyTPA-mediated photodynamic therapy (PDT) to release tumor-associated antigens.
Main Results:
- The developed GCP/miR-140 nanoparticles effectively disassemble within tumor cells.
- Simultaneous downregulation of PD-L1 at both protein (via GO203 binding to MUC1) and mRNA levels (via miR-140).
- PDT induces tumor-associated antigen release, stimulating immune cell-mediated tumor cell attack.
Conclusions:
- The multi-mechanism strategy achieves deep PD-L1 downregulation in tumor cells.
- This approach successfully activates the immune system for effective cancer immunotherapy.
- The novel nanoparticle probe offers a promising platform for advanced oncology treatments.
