Biomimetic engineering peptidyl-based vehicles for efficient mRNA delivery

Antigen-encoding mRNA has emerged as a potent approach to prevent or treat various diseases, yet its clinical application necessitates consideration of reactogenicity and tolerability issues associated with existing delivery systems. The development of novel LNP-alternative delivery platforms represents a critical endeavor. Here, by screening and modifying functionalized motifs of an endogenous retrovirus-like protein, we developed a single-component engineered peptidyl-based vehicle, H3M1-5, which enables desirable biocompatibility, flexible modularity, and efficient mRNA delivery both in vitro and in vivo. H3M1-5 mediated potent delivery of linear mRNA, circular mRNA, and plasmid DNA, with an efficacy comparable to that of the leading commercial transfection reagent. The peptidyl-based mRNA vaccines efficiently facilitated germinal center responses and elicited robust immune responses. Notably, H3M1-5@M1R mRNA significantly protected mice in a lethal challenge model of Orthopoxvirus, and H3M1-5@OVA mRNA delayed tumor growth in both prophylactic and therapeutic B16-OVA melanoma models. Importantly, in contrast to LNP formulations, the peptidyl-based mRNA vaccines didn't trigger a detectable pro-inflammatory response and had a restricted transgene expression in the injection site. This work demonstrates a promising biomimetic strategy for designing simple and efficient peptidyl-based vehicles for mRNA vaccines with favorable safety profiles.