Supramolecular Lipid Nanoparticles Based on Host-Guest Recognition: A New Generation Delivery System of mRNA Vaccines For Cancer Immunotherapy

Dendritic cell (DC) maturation is a crucial process for antigen presentation and the initiation of T cell-mediated immune responses. Toll-like receptors play pivotal roles in stimulating DC maturation and promoting antigen presentation. Here, a novel message RNA (mRNA) cancer vaccine is reported that boosts antitumor efficacy by codelivering an mRNA encoding tumor antigen and a TLR7/8 agonist (R848) to DC using supramolecular lipid nanoparticles (SMLNP) as a delivery platform, in which a new ionizable lipid (N2-3L) remarkably enhances the translation efficiency of mRNA and a beta-cyclodextrin (beta-CD)-modified ionizable lipid (Lip-CD) encapsulates R848. The incorporation of R848 adjuvant into the mRNA vaccine through noncovalent host-guest complexation significantly promotes DC maturation and antigen presentation after vaccination, thus resulting in superior antitumor efficacy in vivo. Moreover, the antitumor efficacy is further boosted synergized with immune checkpoint blockade by potentiating the anticancer capability of cytotoxic T lymphocytes infiltrated in tumor sites. This work indicates that SMLNP shows brilliant potential as next-generation delivery system in the development of mRNA vaccines with high efficacy. Supramolecular lipid nanoparticles (SMLNP) are developed to codeliver mRNA and an adjuvant (R848) through host-guest recognition, showing brilliant potentials in cancer immunotherapy. SMLNP@mRNAOVA/R848 significantly increases the translation efficiency, stimulates DC maturation, and promotes antigen presentation, thus eliciting potent antitumor immune responses. Excitingly, the antitumor performances of mRNA vaccine are further potentiated by synergizing with immune checkpoint blockade. image