Comment on “Self-Illuminating Nanoagonist Simultaneously Induces Dual Cell Death Pathways via Death Receptor Clustering for Cancer Therapy”

Abstract

The study describes a self-illuminating nanoparticle that displays selective antitumoral activity. (1) The nanovector’s antitumoral properties are attributed to the TRAIL receptor 2 (DR5) peptidomimetic, whose cross-linking, induced by a smart H₂O₂-responsive self-illuminating nanoagonist, strongly activates the extrinsic pro-apoptotic signaling pathway. This activation was evidenced in vitro by flow cytometry. The antitumoral efficacy of this smart system was also assessed in vivo using the syngeneic 4T1 tumor breast cancer model. The study shows that the smart nanovector not only prevents tumor growth, achieving more than 82% tumor suppression compared to controls, but also displayed anti-metastatic properties. The manuscript is based on the assumption that the DR5-specific peptide used (WDCLDNRIGRRQCVL), which is known to target human DR5, cross-reacts with the unique mouse TRAIL receptor agonist. (2) While it is true that most ligands of the tumor necrosis factor superfamily (TNFSF), including TRAIL, (3) cross-react between human and mouse orthologues, (4) it should be kept in mind that some members such as GITR/GITRL or APRIL/BAFF-R are strictly species-specific. (4) The first peptide described to display TRAIL-like pro-apoptotic activity was obtained from a peptide scan library composed of 8 amino acids derived from TRAIL itself (see Table 1). Out of the 6 peptides found to trigger apoptosis the most efficient candidate, RNSCWSKD, corresponded to TRAIL aa227-234. (5) Subsequent single amino acid substitution of this sequence revealed a potent peptide CNSCWSKD whose pro-apoptotic activity was shown to engage both DR4 and DR5 (ref (6); see also Table 1), which is consistent with the fact that this peptide derives from TRAIL. However, the DR5-specific peptide used in You et al.’s study is unrelated to TRAIL, (7) and as shown in Table 1, all studies reporting its use, (7−20) so far, only described the use of human cells to assess the biological activity of their formulation (Table 1). In addition, this peptide has, early on, been described to be highly specific for human DR5 and not able to bind to mouse TRAIL receptor. (11,16) Likewise, surface plasmon resonance (SPR) assessments found this peptide unable to bind to human DR4 and the mouse TRAIL receptor. (11) In You’s manuscript, the only evidence of a potential interaction between their smart nanoparticle and the mouse TRAIL receptor is provided by confocal immunofluorescence staining and a FRET assay that show the vicinity of the formulation with the murine TRAIL receptors. While these experiments are interesting, and despite the fact their nanovector displays antitumoral activity, the mere coincident proximity of the receptor and the nanovector is not a strong argument for demonstrating the interaction. The antitumoral efficacy of the formulation may not even rely on the ability of the peptide to engage mouse TRAIL receptor aggregation. Addressing the selective binding of this peptide to the mouse TRAIL receptor would strengthen the author’s conclusions and broaden the potential use of this DR5 peptidomimetic for experimental design requiring the use of mouse cell lines or models. O.M. is supported by grants from the ANR (Agence Nationale de la Recherche) program “Investissements d’Avenir” Labex LipSTIC (ANR-11-LABX-0021-01), ANR ISITE-BFC (ANR-15-IDEX-0003), and ANR LabCom IAM-IT (ANR-22-LCV1-0005-01), the Conseil Regional de Bourgogne, the European commission’s Horizon 2020 Research and Innovation Program DISCOVER (777995), and CHIRON (101130240). The DesCarTes team is supported by the INSERM and the Université de Bourgogne. This article references 20 other publications. This article is cited by 1 publications.