Efficient Induction of Antigen-Specific CD8+ T-Cell Responses by Cationic Peptide-Based mRNA Nanoparticles

Abstract

A major determinant for the success of mRNA-based vaccines is the composition of the nanoparticles (NPs) used for formulation and delivery. Cationic peptides represent interesting candidate carriers for mRNA, since they have been shown to efficiently deliver nucleic acids to eukaryotic cells. mRNA NPs based on arginine-rich peptides have previously been demonstrated to induce potent antigen-specific CD8+ T-cell responses. We therefore compared the histidine-rich amphipathic peptide LAH4-L1 (KKALLAHALHLLALLALHLAHALKKA) to the fully substituted arginine variant (LAH4-L1R) for their capacity to formulate mRNA and transfect dendritic cells (DCs). Although both peptides encapsulated mRNA to the same extent, and showed excellent uptake in DCs, the gene expression level was significantly higher for LAH4-L1. The LAH4-L1–mRNA NPs also resulted in enhanced antigen presentation in the context of MHC I compared to LAH4-L1R in primary murine CD103+ DCs. Both peptides induced DC maturation and inflammasome activation. Subsequent ex vivo stimulation of OT-I splenocytes with transfected CD103+ DCs resulted in a high proportion of polyfunctional CD8+ T cells for both peptides. In addition, in vivo immunization with LAH4-L1 or LAH4-L1R–mRNA NPs resulted in proliferation of antigen-specific T cells. In conclusion, although LAH4-L1 outperformed LAH4-L1R in terms of transfection efficiency, the immune stimulation ex vivo and in vivo was equally efficient.

An Overview of Nanoparticle-Based Delivery Platforms for Vaccines

“…Moreover, cationic peptides as candidate carriers for mRNA have been shown to efficiently deliver nucleic acids to eukaryotic cells. A cationic peptide-based mRNA nanoparticles could induce efficient antigenspecific CD8 + T cell responses [88]. Peptide-based mRNA delivery systems show promise in the field of gene therapy, enabling the delivery of therapeutic mRNA to correct genetic disorders.…”

N‐terminal modification of an LAH4‐derived peptide increases mRNA delivery in the presence of serum

“…Among those CPPs, the cationic amphipathic histidine-rich LAH4 family stood out for its ability to transport a variety of cargoes including DNA [23][24][25], siRNA [26], proteins [27], peptide antigens [28], retroviruses [29][30][31], adeno-associated viruses [32], and quantum dots [33]. Now, in addition to those delivery capabilities, two recent reports showed that the LAH4-L1-derived LAH4 peptide also possesses mRNA delivery capacities [34,35]. Moreover, in 2023, Xu et al reported that a PEGylated LAH4-L1 peptide (PEG 12 -LAH4-L1) efficiently delivers mRNA into tumor cells [36].…”