Adjuvant-pulsed mRNA vaccine nanoparticle for immunoprophylactic and therapeutic tumor suppression in mice

Abstract Synthetic mRNA represents an exciting cancer vaccine technology to the implementation of effective cancer immunotherapy. However, inefficient in vivo mRNA delivery along with a requirement for immune co-stimulation present major hurdles to achieving anti-tumor therapeutic efficacy. Here, we demonstrate a proof-of-concept adjuvant-pulsed mRNA vaccine nanoparticle (NP) that is composed of an ovalbumin-coded mRNA and a palmitic acid-modified TLR7/8 agonist R848 (C16-R848), coated with a lipid-polyethylene glycol (lipid-PEG) shell. This mRNA vaccine NP formulation retained the adjuvant activity of encapsulated C16-R848 and markedly improved the transfection efficacy of the mRNA (>95%) and subsequent MHC class I presentation of OVA mRNA derived antigen in antigen-presenting cells. The C16-R848 adjuvant-pulsed mRNA vaccine NP approach induced an effective adaptive immune response by significantly improving the expansion of OVA-specific CD8+ T cells and infiltration of these cells into the tumor bed in vivo, relative to the mRNA vaccine NP without adjuvant. The approach led to an effective anti-tumor immunity against OVA expressing syngeneic allograft mouse models of lymphoma and prostate cancer, resulting in a significant prevention of tumor growth when the vaccine was given before tumor engraftment (84% reduction vs. control) and suppression of tumor growth when given post engraftment (60% reduction vs. control). Our findings indicate that C16-R848 adjuvant pulsation to mRNA vaccine NP is a rational design strategy to increase the effectiveness of synthetic mRNA vaccines for cancer immunotherapy.