期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 39, 页码 E9153-E9161出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1810002115
关键词
cancer vaccination; mRNA; nanoparticles; T cell responses; immunotherapy
资金
- NIH [R35CA197353]
- National Science Foundation [CHE-1607092]
- NIH Grants [CA031841, CA031845]
- Norwegian Cancer Society
- Norwegian Health Authorities
- Stanford Cancer Translational Nanotechnology Training T32 Training Grant - National Cancer Institute [CA196585]
- Stanford Center for Molecular Analysis and Design
- NIH S10 Shared Instrument Grant [S10RR027431-01]
- NATIONAL CANCER INSTITUTE [T32CA196585, R01CA031845, R37CA031845, R35CA197353, R37CA031841, R01CA031841] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027431] Funding Source: NIH RePORTER
In vivo delivery of antigen-encoding mRNA is a promising approach to personalized cancer treatment. The therapeutic efficacy of mRNA vaccines is contingent on safe and efficient gene delivery, biological stability of the mRNA, and the immunological properties of the vaccine. Here we describe the development and evaluation of a versatile and highly efficient mRNA vaccine-delivery system that employs charge-altering releasable transporters (CARTs) to deliver antigen-coding mRNA to antigen-presenting cells (APCs). We demonstrate in human peripheral blood mononuclear cells that CART vaccines can activate a robust antigen-specific immune response against mRNA-encoded viral epitopes. In an established mouse model, we demonstrate that CARTs preferentially target professional APCs in secondary lymphoid organs upon i.v. injections and target local APCs upon s.c. injection. Finally, we show that CARTs coformulated with mRNA and a Toll-like receptor ligand simultaneously transfect and activate target cells to generate an immune response that can treat and cure mice with large, established tumors.
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