Rui Wang, Lin Bao, Yiyan Yu, Runhe Zhang, Zhongyuan Guo, Luke J. Kubiatowicz, Nishta Krishnan, Ilkoo Noh, Edward Wang, Ronnie H. Fang, Weiwei Gao, Liangfang Zhang
Bacterial outer membrane vesicles (OMVs) possess intrinsic immunostimulatory properties by carrying native antigens and pathogen-associated molecular patterns (PAMPs). Lipid nanoparticles (LNPs) have become the leading platform for messenger ribonucleic acid (mRNA) delivery, underpinning the clinical success of mRNA vaccines. Here, we developed a hybrid nanoparticle formulation, OMV-coated LNPs (OMV-LNPs), that combines the high delivery efficiency of LNPs with the immunogenicity of the OMVs to enhance gene delivery. Using Escherichia coli -derived OMVs and dengue virus (DENV) E80 protein as a model antigen, we generated OMV-LNPs encapsulating DENV mRNA (OMV-LNP mRNA ). These nanoparticles demonstrated improved uptake by lymph-node-resident immune cells and enhanced cytosolic mRNA delivery, resulting in robust dendritic cell maturation and proinflammatory cytokine production in vitro . In AG129 mice, the OMV-LNP mRNA elicited significantly higher titers of DENV-neutralizing antibodies compared to conventional LNPs. Collectively, these results establish OMV-LNPs as a versatile and potent platform for effective mRNA vaccine delivery.