Delivery of mRNA Vaccines With Heterocyclic Lipids Increases Anti-Tumor Efficacy by STING-mediated Immune Cell Activation

Nat Biotechnol. 2019 Oct;37(10):1174-1185. doi: 10.1038/s41587-019-0247-3. Epub 2019 Sep 30.


Therapeutic messenger RNA vaccines enable delivery of whole antigens, which can be advantageous over peptide vaccines. However, optimal efficacy requires both intracellular delivery, to allow antigen translation, and appropriate immune activation. Here, we developed a combinatorial library of ionizable lipid-like materials to identify mRNA delivery vehicles that facilitate mRNA delivery in vivo and provide potent and specific immune activation. Using a three-dimensional multi-component reaction system, we synthesized and evaluated the vaccine potential of over 1,000 lipid formulations. The top candidate formulations induced a robust immune response, and were able to inhibit tumor growth and prolong survival in melanoma and human papillomavirus E7 in vivo tumor models. The top-performing lipids share a common structure: an unsaturated lipid tail, a dihydroimidazole linker and cyclic amine head groups. These formulations induce antigen-presenting cell maturation via the intracellular stimulator of interferon genes (STING) pathway, rather than through Toll-like receptors, and result in limited systemic cytokine expression and enhanced anti-tumor efficacy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / metabolism
  • Antineoplastic Agents* / pharmacokinetics
  • Antineoplastic Agents* / pharmacology
  • Cancer Vaccines* / chemistry
  • Cancer Vaccines* / genetics
  • Cancer Vaccines* / pharmacokinetics
  • Cancer Vaccines* / pharmacology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Female
  • HeLa Cells
  • Humans
  • Interferons / genetics
  • Interferons / metabolism
  • Lipids / pharmacokinetics*
  • Mice
  • Mice, Inbred C57BL
  • Pharmaceutical Vehicles* / chemistry
  • Pharmaceutical Vehicles* / pharmacokinetics
  • RNA, Messenger* / genetics
  • RNA, Messenger* / pharmacokinetics
  • RNA, Messenger* / pharmacology
  • Signal Transduction / drug effects
  • Small Molecule Libraries


  • Antineoplastic Agents
  • Cancer Vaccines
  • Lipids
  • Pharmaceutical Vehicles
  • RNA, Messenger
  • Small Molecule Libraries
  • Interferons