Multi-antigen spherical nucleic acid cancer vaccines

Teplensky, Michelle H.; Evangelopoulos, Michael; Dittmar, Jasper W.; Forsyth, Connor M.; Sinegra, Andrew J.; Wang, Shuya; Mirkin, Chad A.

doi:10.1038/s41551-022-01000-2

Cited by 49 publications

(25 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To gain an understanding of how improvements in stability affect the SNA’s biological properties, we studied the interactions of SNAs with murine bone marrow-derived dendritic cells (BMDCs) since immunostimulatory SNAs are known to interact with DCs to generate robust T cell responses in vivo. ,, As cellular uptake of SNAs depends on the density of oligonucleotides on the surface, we hypothesized the enhanced stability of the C12 oligomers would also enhance SNA uptake and activation of BMDCs via the Toll-like receptor 9 (TLR9) pathway. To ensure that the (C12) 9 anchor did not alter cellular entry, we used confocal microscopy (Figure ) to confirm uptake into BMDCs for both cholesterol and (C12) 9 SNAs.…”

Section: Resultsmentioning

confidence: 99%

“…SNAs not only offer a way to improve liposomal formulations and elevate the delivery of nucleic acid cargo, but they also have properties distinct from their linear nucleic acid components. − In contrast with linear nucleic acids, SNAs rapidly enter cells, resist nuclease degradation, and exhibit higher binding constants for their complements when compared to free strands of the same sequence . These SNA properties have led to the development of several nucleic acid-based nanomedicines that are under evaluation in multiple clinical trials. − Liposomal SNAs, in particular, are a promising platform to design vaccines by manipulating their structure at the nanoscale, − thereby enabling the investigation of structure–function relationships driving enhanced immune activity: an approach termed rational vaccinology . Through this approach, various features have been identified as being critical in elevating vaccine potency. , For example, the stability of these structures has been shown to impact their pharmacokinetic profile, and high-throughput methods have identified anchor chemistry as a vital parameter in the design of SNA vaccines .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tuning DNA Dissociation from Spherical Nucleic Acids for Enhanced Immunostimulation

Dittmar,

Teplensky,

Evangelopoulos

et al. 2023

ACS Nano

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Tuning DNA Dissociation from Spherical Nucleic Acids for Enhanced Immunostimulation

Dittmar,

Teplensky,

Evangelopoulos

et al. 2023

ACS Nano

Self Cite

View full text Add to dashboard Cite

show abstract

“…Through SNAs and this approach, we have shown that targets that had previously failed out of clinical trials could gain potency when arranged in a properly structured SNA formulation . Furthermore, multiple antigens have been incorporated in SNA vaccines, and the importance of antigen release kinetics on potency has been determined . Given the thousands of possible SNA (and PAE) formulations, combinatorial and machine learning approaches have been brought to bear on SNA therapeutic design to find the most potent structures with Andrew Lee, Neda Bagheri, and Milan Mrksich and their teams …”

Section: The Birth and Growth Of A New Field Of Chemistrymentioning

confidence: 99%

Inspired Beyond Nature: Three Decades of Spherical Nucleic Acids and Colloidal Crystal Engineering with DNA

Mirkin

Petrosko

2023

ACS Nano

Self Cite

View full text Add to dashboard Cite

The conception, synthesis, and invention of a nanostructure, now known as the spherical nucleic acid, or SNA, in 1996 marked the advent of a new field of chemistry. Over the past three decades, the SNA and its analogous anisotropic equivalents have provided an avenue for us to think about some of the most fundamental concepts in chemistry in new ways and led to technologies that are significantly impacting fields from medicine to materials science. A prime example is colloidal crystal engineering with DNA, the framework for using SNAs and related structures to synthesize programmable matter. Herein, we document the evolution of this framework, which was initially inspired by nature, and describe how it now allows researchers to chart paths to move beyond it, as programmable matter with real-world significance is envisioned and created.

show abstract

“…164 This is observed with oligonucleotidebased nanocarriers, such as SNAs. [165][166][167] SNAs can incorporate PRR agonists or antagonists for receptor-mediated targeting to bias the innate immune response towards specific phenotypes. 168 SNAs are composed of oligonucleotides arranged radially around a nanoparticle core; they are preferentially taken up compared to free linear oligonucleotides in over 60 cell types due to their multivalent interactions with scavenger receptors on the cell surface resulting in caveolaemediated endocytosis.…”

Section: Uptake and Targetingmentioning

confidence: 99%