Résumé
Short interfering RNA (siRNA) are promising tools that can induce a specific downregulation of a targeted gene. However, their low metabolic stability, cell selectivity, and their inability to cross biological barriers conditioned their clinical application to the use of a specific drug delivery system. In this context, peptide-based nanoparticles (PBNs) have been extensively developed for the intracellular transport of nucleic acids (Boisguérin et al. 2021).Recently we designed a new family of amphipathic peptides called WRAP (W- and R-rich Amphipathic Peptides) which are able to self-assemble in PBNs once incubated with a given ratio of siRNA (Konate et al. 2019). The high efficacy of our WRAP-PBNs to deliver siRNAs in different cell lines was mostly due to its direct cellular membrane translocation, even if a minority fraction entered via endocytosis-dependent pathways. WRAP-PBNs were also able to destabilize artificial membranes which was probably the key step for potentiating siRNA activity (Deshayes et al. 2020).A structure-activity relationship (SAR) study investigating the role of WRAP residues on nanoparticle formation and gene silencing activity revealed the main role of N- and C-terminal leucine doublets (Konate et al. 2021). Moreover after a comparison of WRAP-PBNs to commercially available siRNA-transfection reagents (RNAiMAX, etc), the optimal WRAP sequences were associated to a cell-targeting peptide (CTP) as well as a PEG moiety in order to design multi-grafted WRAP-PBNs. We showed that the nanoparticle formation and more importantly siRNA activity were not disturbed by the grafting of a low percentage (10%-20%) of CTP or PEG. Finally a first in vivo investigation demonstrated an effective knock down in a mouse xenograft model (Ferreiro et al. 2021).In conclusion, WRAP-PBNs could be used as efficient delivery agent to silence the expression of any kind of genes in a wide number of cells as well as in vivo in solid tumors.