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

Autor: Wan WJ; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Huang G; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Wang Y; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Tang Y; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Li H; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Jia CH; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Liu Y; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., You BG; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Zhang XN; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China. Electronic address: zhangxuenong@163.com.
Jazyk: angličtina
Zdroj: Acta biomaterialia [Acta Biomater] 2021 Dec; Vol. 136, pp. 473-484. Date of Electronic Publication: 2021 Sep 24.
DOI: 10.1016/j.actbio.2021.09.040
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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