Coadministration of iRGD peptide with ROS-sensitive nanoparticles co-delivering siFGL1 and siPD-L1 enhanced tumor immunotherapy. (December 2021)

• Record Type: Journal Article
• Authors: Wan, Wen-jun; Huang, Gui; Wang, Yu; Tang, Yan; Li, Hui; Jia, Chang-hao; Liu, Yang; You, Beng-gang; Zhang, Xue-nong
• Is Part Of: Acta biomaterialia. Volume 136(2021)
• Page Start: 473
• Page End: 484
• Publication Date: 2021-12
• Subjects: Immune checkpoint -- ROS sensitive -- Nano-delivery system -- Immunotherapy; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2021.09.040
• Languages: English
• ISSNs: 1742-7061

Abstract

Abstract: The continuous activation and expansion of tumor-specific T cells by various means are the main goal of cancer immunotherapy. Tumor cells overexpress fibrinogen-like protein 1 (FGL1) and programmmed death-ligand 1 (PD-L1), which respectively bind to lymphocyte-activation gene 3 (LAG-3) and programmmed death-1(PD-1) on T cells, forming important signaling pathways (FGL1/LAG-3 and PD-1/PD-L1) that negatively regulate immune responses. In order to interfere with the inhibitory function of FGL1 and PD-L1 proteins, we designed a new type of reactive oxygen species (ROS)-sensitive nanoparticles to load FGL1 siRNA (siFGL1) and PD-L1 siRNA (siPD-L1), which was formed from a stimuli-responsive polymer with a poly-l -lysine–thioketal and modified cis -aconitate to facilitate endosomal escape. Moreover, tumor-penetrating peptide iRGD and ROS-responsive nanoparticles were co-administered to further enhance the delivery efficiency of siFGL1 and siPD-L1, thereby significantly reducing the protein levels of FGL1 and PD-L1 in tumor cells. Our findings indicated that the dual delivery of FGL1/PD-L1 siRNA was a new and powerful treatment method, which was characterized by increasing the infiltration of effector CD4+ and CD8+ T cells, effectively alleviating the tumor immunosuppressive microenvironment. These findings also supported the superiority and feasibility of nanoparticle-mediated tumor immunotherapy, and may provide a different perspective for cancer treatment. Statement of significance: In addition to the idea that cancer vaccines can promote T cell immune responses, nanoparticle delivery modulators (such as small interfering RNA (siRNA) targeting immunosuppressive pathways) may provide more information for the research of nanoparticle-mediated cancer immunotherapy. In this study, we designed a new intelligent nano-delivery system for co-delivery of siFGL1 and siPD-L1, and demonstrated the ability to down-regulate the expression levels of FGL1 and PD-L1 proteins in tumor cells in vitro and in vivo. The constructed nanoparticle had a good tumor microenvironment responsiveness, and the delivery efficiency was enhanced by co-injection with tumor penetrating peptide iRGD. This project proposed a new strategy for tumor immunotherapy based on smart nano-delivery systems, and explored more possibilities for tumor therapy. Graphical abstract: Image, graphical abstract