Abstract
Immunostimulatory spherical nucleic acids (IS-LSNAs) comprised of RNA selective for toll-like receptors (TLRs) 7/8 are synthesized and characterized. These structures consist of liposomal cores functionalized with a dense shell of RNA inserted into the wall of the lipid core via hydrophobic cholesterol moieties. IS-LSNAs potently activate TLR7/8 via NF-κΒ signaling in reporter cell lines and in primary immune cells as evidenced by cytokine production and the upregulation of costimulatory receptors. Importantly, they are preferentially taken up by plasmacytoid dendritic cells, an observation that makes them potentially useful for immunotherapy. In addition, these structures contain a core that can be loaded with antigens and used to prime T cells. In this regard, it is shown that dendritic cells treated with IS-SNAs loaded with ovalbumin peptide can prime ova specific CD8+ T cells. In addition to introducing the first IS-LSNAs consisting of RNA, these experiments show that one can facilitate an antigen-specific T cell response greater than that of free or cationic lipid-transfected RNA of the same sequence selective for TLR7/8. This work points toward the promise of using IS-LSNAs comprised of RNA as potent and highly tunable TLR-specific agents for the development of vaccines and other pharmaceuticals that require selective immunomodulation.
| Original language | English (US) |
|---|---|
| Article number | 1803284 |
| Journal | Small |
| Volume | 14 |
| Issue number | 49 |
| DOIs | |
| State | Published - Dec 6 2018 |
Funding
C.G. and N.C. contributed equally to this work. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award No. U54CA199091 and the Prostate Cancer Foundation and Movember Foundation under Award No. 17CHAL08. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. C.A.M. also gratefully acknowledges support from the NTU-NU Institute for NanoMedicine located at the International Institute for Nanotechnology, Northwestern University, USA, and the Nanyang Technological University, Singapore. C.G. was supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program. L.C. was supported by Northwestern University’s Cancer Nanotechnology Training Program under Award No. T32CA186897. Liposome concentration was determined using the ICP-OES at the Northwestern University Quantitative Bioelemental Imaging Center. Flow cytometry was conducted at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core. CryoEM images were taken with help from Dr. Jonathan Remis. The authors acknowledge staff and instrumentation support from the Structural Biology Facility at Northwestern University, the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and NCI CCSG P30 CA060553. C.G. and N.C. contributed equally to this work. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award No. U54CA199091 and the Prostate Cancer Foundation and Movember Foundation under Award No. 17CHAL08. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. C.A.M. also gratefully acknowledges support from the NTU-NU Institute for NanoMedicine located at the International Institute for Nanotechnology, Northwestern University, USA, and the Nanyang Technological University, Singapore. C.G. was supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program. L.C. was supported by Northwestern University's Cancer Nanotechnology Training Program under Award No. T32CA186897. Liposome concentration was determined using the ICP-OES at the Northwestern University Quantitative Bioelemental Imaging Center. Flow cytometry was conducted at Northwestern University's Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core. CryoEM images were taken with help from Dr. Jonathan Remis. The authors acknowledge staff and instrumentation support from the Structural Biology Facility at Northwestern University, the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and NCI CCSG P30 CA060553.
Keywords
- SNAs
- TLR7/8 agonist
- cancer vaccine
- immunomodulation
- liposome
- nanoparticle
- spherical nucleic acids
ASJC Scopus subject areas
- Biotechnology
- General Chemistry
- Biomaterials
- General Materials Science
- Engineering (miscellaneous)
