Therapeutic mRNA vaccines have developed rapidly in recent years, and they have attracted wide attention as a new choice for tumor treatment. Through precise sequence design, mRNA vaccines can encode one or more tumor-specific antigens (TSA), and after protein translation and antigen processing, they can bind to major histocompatibility antigen complex I (MHCI) in antigen-presenting cells, and finally present them to T cells to induce strong tumor-specific T cell responses and kill tumor cells.

This method of intracellular antigen production and processing used by mRNA vaccines is particularly suitable for tumor vaccines because this pathway simulates the natural production of tumor antigens in cancer cells. Entry into antigen-presenting cells is a prerequisite for mRNA tumor vaccines to effectively activate immunity. Because of its poor stability, high molecular weight and high negative charge, mRNA must rely on powerful delivery carriers to enter cells effectively.

At present, the clinical mRNA carriers used for in vivo delivery are mainly lipid nanoparticles (LNP). mRNA is encapsulated into nano-carriers through the synthesis of microfluidic. Due to the heterogeneity and complexity of tumor antigens, this time-consuming encapsulation process is not suitable for the customized production of personalized tumor vaccines. In addition, successful adaptive immune activation requires the help of innate immunity, so mRNA tumor vaccines usually require co-administration of immune adjuvants, which makes its preparation more complex.

Therefore, there is an urgent need for a new nano-carrier which can quickly display mRNA antigen and has the function of innate immunostimulation, in order to further develop personalized tumor vaccine based on mRNA.

Recently, Nie Guangjun’s team of researchers published a research paper entitled Rapid surface display of mRNA antigens by bacteria-derived outer membrane vesicles for a personalized tumor vaccine in the journal Advanced Materials.

Outer membrane vesicles (OMVs) are nano-sized natural vesicles secreted by Gram-negative bacteria, which can be effectively recognized and absorbed by dendritic cells (the main antigen-presenting cells). In addition, OMVs have rich pathogen-associated molecular patterns (PAMPs), which can strongly stimulate the innate immune system and promote antigen presentation and T cell activation.

OMVs are an ideal vaccine nano-carrier, which has attracted a lot of attention in the development of vaccines against pathogenic microorganisms, because they can display and deliver foreign antigens from target microorganisms through fusion expression with scaffold proteins on OMVs.

Previously, Nie Guangjun’s team used genetic engineering and molecular gel technology to modify OMVs to build an OMVs-based nano-carrier platform with a “plug and play” function. This platform can quickly display tumor antigens based on peptides, and is especially suitable for the rapid preparation of personalized tumor vaccines. However, no research has been done to explore the use of OMVs platform as an mRNA vaccine delivery vector, and methods to rapidly display mRNA antigens are still limited.

In this study, the team used bacterial-derived outer membrane vesicles (OMVs) as an mRNA delivery platform and genetically modified the RNA-binding protein L7Ae and lysosome escape protein listeria hemolysin O-OMV-LL.

OMV-LL can bind mRNA antigens through L7Ae and deliver them to dendritic cells, and then cross-present them through endosome escape mediated by listeria listeria hemolysin O.

Animal experiments have shown that OMV-LL-mRNA can significantly inhibit the progression of melanoma in mice, resulting in the complete regression of 37.5% of colorectal cancer mouse models. OMV-LL-mRNA can induce long-term immune memory and still protect mice from tumor attack after 60 days.

In general, the genetically engineered outer membrane vesicles (OMVs) of bacteria developed in this study are different from lipid nanoparticles (LNP) delivery vectors. They can be used for personalized mRNA tumor vaccine development with the “plug-and-play” strategy applied, which is expected to be widely used in mRNA vaccines.