Abstract
The synthesis and evaluation of spherical nucleic acids (SNAs) incorporating two physically and chemically distinct classes of oligonucleotides (ODNs) at programmed ratios are described. These SNAs are single entity agents that enter the same target cell at defined stoichiometries, and as such allow one to control important cell signaling and regulatory processes. To study the effect of sequence multiplicity within such structures, we synthesized SNAs consisting of a mixture of class A CpG and class B CpG, immunostimulatory ODNs that activate two different toll-like receptor 9 signaling pathways, each in a sequence-specific fashion. These dual-CpG SNAs exhibit high cellular uptake and codelivery of the two ODNs, relative to mixtures of the linear ODN counterparts, and remain highly associated inside the cell over time. Furthermore, the dual-CpG SNAs augment dendritic cell maturation, compared to the same amounts of oligonucleotides delivered in linear or SNA form but not conjugated to one another. Consequently, these structures constitute a platform for designing oligonucleotide-based combination therapeutics with highly tailorable activities.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1084-1092 |
| Number of pages | 9 |
| Journal | ACS nano |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 28 2020 |
Funding
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under awards U54CA199091 and R01CA208783. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The project was also supported by the Prostate Cancer Foundation and the Movember Foundation under award 17CHAL08, and the IDP Sherman Fairchild Foundation through the Robert H. Lurie Comprehensive Cancer Center. This work made use of the IMSERC at Northwestern University and EPIC facility of Northwestern University’s NUANCE Center, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois through the IIN. Confocal microscopy was partially performed at the Biological Imaging Facility at Northwestern University, graciously supported by the Chemistry for Life Processes Institute, the NU Office for Research, and the Rice Foundation. Computation was supported in part through the computational resources provided for the Quest high performance computing facility at Northwestern University which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. Flow cytometry was supported by the Northwestern University Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). Z.N.H. acknowledges support by the Northwestern University Graduate School Cluster in Biotechnology, Systems, and Synthetic Biology, which is affiliated with the Biotechnology Training Program funded by NIGMS Grant T32 GM008449. L.E.C. acknowledges support from Northwestern University’s Cancer Nanotechnology Training Program award T32CA186897. C.E.C. acknowledges support from the Eden and Steven Romick Post-Doctoral Fellowship through the American Committee for the Weizmann Institute of Science. S.W. was supported by a fellowship associated with the Chemistry of Life Processes Predoctoral Training Program T32GM105538 at Northwestern University.
Keywords
- DNA nanotechnology
- biotechnology
- immunotherapy
- microscopy
- spherical nucleic acids
ASJC Scopus subject areas
- General Engineering
- General Physics and Astronomy
- General Materials Science