Using an in vitro antigen presentation screen, Zhang and You et al. selected a cationic lipid-like compound (C1) that condensed mRNA via electrostatic interactions and self-assembled with PEG to form stable nanoparticles (NPs). NPs phagocytosed by DCs activated TLR4 to induce DCs to mature and make inflammatory cytokines. In DCs, NP mRNA was translated, and the peptide–MHC-I complexes that formed induced specific murine CD8+ T cell responses in vitro and in vivo. In melanoma and colorectal tumor line mouse models, NPs delivering mRNA encoding tumor antigens induced preventive and regressive antitumor effects, dependent on TLR4, without notable toxicity.
Contributed by Paula Hochman
ABSTRACT: Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.