Development of Mannosylated Lipid Nanoparticles for mRNA Cancer Vaccine with High Antigen Presentation Efficiency and Immunomodulatory Capability

Abstract

AbstractInsufficient accumulation of lipid nanoparticles (LNPs)‐based mRNA vaccines in antigen presenting cells remains a key barrier to eliciting potent antitumor immune responses. Herein, we develop dendritic cells (DCs) targeting LNPs by taking advantage of mannose receptor‐mediated endocytosis. Efficient delivery of mRNA to DCs is achieved in vitro and in vivo utilizing the sweet LNPs (STLNPs‐Man). Intramuscular injection of mRNA vaccine (STLNPs‐Man@mRNAOVA) results in a four‐fold higher uptake by DCs in comparison with commercially used LNPs. Benefiting from its DCs targeting ability, STLNPs‐Man@mRNAOVA significantly promotes the antitumor performances, showing a comparable therapeutic efficacy by using one‐fifth of the injection dosage as the vaccine prepared from normal LNPs, thus remarkably avoiding the side effects brought by conventional mRNA vaccines. More intriguingly, STLNPs‐Man@mRNAOVA exhibits the ability to downregulate the expression of cytotoxic T‐lymphocyte‐associated protein 4 on T cells due to the blockade of CD206/CD45 axis, showing brilliant potentials in promoting antitumor efficacy combined with immune checkpoint blockade therapy.