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Review
. 2023 Feb 3;15(2):515.
doi: 10.3390/pharmaceutics15020515.

Recent Advances in the Development of Nanodelivery Systems Targeting the TRAIL Death Receptor Pathway

Anne V Yagolovich  1   2 , Marine E Gasparian  1 , Dmitry A Dolgikh  1   2
Affiliations
Review

Recent Advances in the Development of Nanodelivery Systems Targeting the TRAIL Death Receptor Pathway

Anne V Yagolovich et al. Pharmaceutics. .

Abstract

The TRAIL (TNF-related apoptosis-inducing ligand) apoptotic pathway is extensively exploited in the development of targeted antitumor therapy due to TRAIL specificity towards its cognate receptors, namely death receptors DR4 and DR5. Although therapies targeting the TRAIL pathway have encountered many obstacles in attempts at clinical implementation for cancer treatment, the unique features of the TRAIL signaling pathway continue to attract the attention of researchers. Special attention is paid to the design of novel nanoscaled delivery systems, primarily aimed at increasing the valency of the ligand for improved death receptor clustering that enhances apoptotic signaling. Optionally, complex nanoformulations can allow the encapsulation of several therapeutic molecules for a combined synergistic effect, for example, chemotherapeutic agents or photosensitizers. Scaffolds for the developed nanodelivery systems are fabricated by a wide range of conventional clinically approved materials and innovative ones, including metals, carbon, lipids, polymers, nanogels, protein nanocages, virus-based nanoparticles, dendrimers, DNA origami nanostructures, and their complex combinations. Most nanotherapeutics targeting the TRAIL pathway are aimed at tumor therapy and theranostics. However, given the wide spectrum of action of TRAIL due to its natural role in immune system homeostasis, other therapeutic areas are also involved, such as liver fibrosis, rheumatoid arthritis, Alzheimer's disease, and inflammatory diseases caused by bacterial infections. This review summarizes the recent innovative developments in the design of nanodelivery systems modified with TRAIL pathway-targeting ligands.

Keywords: DR5; TRAIL; death receptors; drug delivery; ligand-targeted drugs; nanoparticles; nanotherapeutics; receptor clustering.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Three-dimensional structure of TRAIL in complex with the DR5 receptor retrieved from Protein Data Bank (PDB number 1D4V).
Figure 2
Figure 2
Schematic illustration of S-TRAIL and S-TRAIL/GQD preparation and biological function. Reproduced from [34]. Copyright © 2022, The Authors (CC BY 4.0 http://creativecommons.org/licenses/by/4.0/ (accessed on 20 January 2023)).
Figure 3
Figure 3
Schematic showing the mechanism by which tumor stroma-targeted TRAIL-NO@Nanogel suppresses PDAC progression in mice. NO released from tumor stroma-targeted TRAIL-NO@Nanogel remodels the fibrotic tumor microenvironment of desmoplastic PDAC. (1) NO released from NPs modified with tumor stroma-targeting peptides identified by phage display suppresses PSC activation, reduces ECM production, and increases tumor perfusion in PDAC. (2) NO reprogrammed the desmoplastic stroma and overcomes TRAIL resistance, sensitizing PDAC tumors to TRAIL therapy. (3) Co-delivery of TRAIL and NO by tumor stroma-targeted TRAIL-NO@Nanogel efficiently suppresses tumor growth. ECM, extracellular matrix; NO, nitric oxide; NPs, nanoparticle; PDAC, pancreatic ductal adenocarcinoma; PSC, pancreatic stellate cells; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. Reproduced with permission from [89]. Copyright © 2022, BMJ Publishing Group Ltd. & British Society of Gastroenterology (CC BY-NC 4.0 http://creativecommons.org/licenses/by-nc/4.0/ (accessed on 20 January 2023)).
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