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

Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation.

Miao L1,2, Li L1,2,3, Huang Y1, Delcassian D1,4,5, Chahal J1, Han J3, Shi Y1,2, Sadtler K1,4, Gao W1, Lin J1, Doloff JC1,2,4,6, Langer R1,2,4,7,8, Anderson DG9,10,11,12,13.

Author information

1
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
2
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
3
Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong, China.
4
Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA.
5
Division of Regenerative Medicine and Cellular Therapy, University of Nottingham, Nottingham, UK.
6
Departments of Biomedical & Materials Science Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute and the Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
8
Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
9
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
10
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
11
Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA. dgander@mit.edu.
12
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
13
Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.

Abstract

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.

PMID:
31570898
DOI:
10.1038/s41587-019-0247-3

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