A short peptide for efficient cellular mRNA delivery: A potential application for inducing an immune response

• Published in: Molecular therapy. Nucleic acids Vol. 36; no. 3; p. 102650
• Main Authors: Teko-Agbo, Clémentine Ayélé, Josse, Emilie, Konate, Karidia, Deshayes, Sébastien, de Santa Barbara, Pascal, Faure, Sandrine, Boisguérin, Prisca, Vivès, Eric
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.09.2025; Elsevier; American Society of Gene & Cell Therapy
• Subjects: cell-penetrating peptides; Life Sciences; mRNA delivery; MT: Delivery Strategies; nanoparticle; Original; vaccine; nanoparticle; vaccine; mRNA delivery; MT: Delivery Strategies; cell-penetrating peptides
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2025.102650

Nucleic acid molecules are emerging as potential therapeutic tools, as evidenced by the transfection of small interfering RNA (siRNA) molecules in therapeutic applications and messenger RNAs in immunotherapeutic vaccination. In most cases, these nucleic acids are conditioned as lipid nanoparticles made with different lipid moieties to promote their intracellular delivery. Over the past few years, we have documented the delivery of siRNAs using a single short (15 amino acids) peptide called WRAP5, which follows an extremely simplified formulation phase that enables the formation of nanoparticles with a diameter of 60–80 nm. We indeed demonstrated the expected dose-response reduction in the levels of the targeted proteins. To apply this technology to the cellular delivery of mRNAs, we investigated the ability of the WRAP5 peptide to transfect mRNAs of different sizes and promote the expression of their proteins. These peptide-based nanoparticles, which also have diameters ranging from 60 to 80 nm, showed remarkable stability over time when simply stored at 4°C and fully retained their transfection properties in vitro for up to several months post-formulation. Interestingly, we demonstrated in vivo that these nanoparticles were able to induce an immune response against the protein synthesized from the vectorized mRNA. [Display omitted] Peptide-based nanoparticle (PBN) technology using one single peptide promotes both cellular delivery of mRNAs and expression of the corresponding protein. These PBNs (60–80 nm) showed stability for up to several months when stored at 4°C and induced an immune response against the protein synthesized from the vectorized mRNA.