Abstract
The stability of the core can significantly impact the therapeutic effectiveness of liposome-based drugs. While the spherical nucleic acid (SNA) architecture has elevated liposomal stability to increase therapeutic efficacy, the chemistry used to anchor the DNA to the liposome core is an underexplored design parameter with a potentially widespread biological impact. Herein, we explore the impact of SNA anchoring chemistry on immunotherapeutic function by systematically studying the importance of hydrophobic dodecane anchoring groups in attaching DNA strands to the liposome core. By deliberately modulating the size of the oligomer that defines the anchor, a library of structures has been established. These structures, combined with in vitro and in vivo immune stimulation analyses, elucidate the relationships between and importance of anchoring strength and dissociation of DNA from the SNA shell on its biological properties. Importantly, the most stable dodecane anchor, (C12)9, is superior to the n = 4-8 and 10 structures and quadruples immune stimulation compared to conventional cholesterol-anchored SNAs. When the OVA1 peptide antigen is encapsulated by the (C12)9 SNA and used as a therapeutic vaccine in an E.G7-OVA tumor model, 50% of the mice survived the initial tumor, and all of those survived tumor rechallenge. Importantly, the strong innate immune stimulation does not cause a cytokine storm compared to linear immunostimulatory DNA. Moreover, a (C12)9 SNA that encapsulates a peptide targeting SARS-CoV-2 generates a robust T cell response; T cells raised from SNA treatment kill >40% of target cells pulsed with the same peptide and ca. 45% of target cells expressing the entire spike protein. This work highlights the importance of using anchor chemistry to elevate SNA stability to achieve more potent and safer immunotherapeutics in the context of both cancer and infectious disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 17996-18007 |
| Number of pages | 12 |
| Journal | ACS nano |
| Volume | 17 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 26 2023 |
Funding
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers R01CA257926, P50CA221747, and R01CA275430. M. Teplensky acknowledges support from Northwestern University’s Cancer Nanotechnology Training Program supported by the National Cancer Institute of the National Institutes of Health award T32CA186897. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M. Teplensky also acknowledges support from Edward Bachrach. J. Dittmar was partially supported by a fellowship associated with the Chemistry of Life Processes Predoctoral Training Program at Northwestern University. The content is solely the responsibility of the authors and does not necessarily represent the official views of Northwestern University. M. Evangelopoulos was partially supported by the Dr. John N. Nicholson Fellowship and the Alexander S. Onassis Public Benefit Foundation. This work made use of the IMSERC MS facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), the State of Illinois, and the International Institute for Nanotechnology (IIN). We thank the Immunotherapy Assessment Core at the Robert H Lurie Comprehensive Cancer Center of Northwestern University, and S. Pandey and L. Kai for their assistance with serum cytokine profiling. Peptide synthesis was performed at the Peptide Synthesis Core Facility of the Simpson Querrey Institute for BioNanotechnology at Northwestern University.
Keywords
- biological stability
- immune activation
- immunomodulation
- liposomal spherical nucleic acids
- spherical nucleic acids
ASJC Scopus subject areas
- General Engineering
- General Materials Science
- General Physics and Astronomy
