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Tuning DNA Dissociation from Spherical Nucleic Acids for Enhanced Immunostimulation.

Jasper W Dittmar1, Michelle H Teplensky2, Michael Evangelopoulos1

  • 1Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.

ACS Nano
|September 15, 2023
PubMed
Summary

Optimizing DNA anchoring to spherical nucleic acid (SNA) liposomes enhances drug stability and immune response. The (C12)9 anchor significantly boosts therapeutic vaccine efficacy against cancer and viral infections without adverse effects.

Keywords:
biological stabilityimmune activationimmunomodulationliposomal spherical nucleic acidsspherical nucleic acids

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Area of Science:

  • Biotechnology and Nanomedicine
  • Immunology and Vaccinology

Background:

  • Liposome stability is crucial for drug efficacy, and spherical nucleic acid (SNA) architecture improves this.
  • The chemistry anchoring DNA to liposomes is an underexplored factor influencing biological impact.

Purpose of the Study:

  • To investigate the impact of SNA anchoring chemistry on immunotherapeutic function.
  • To explore the role of hydrophobic dodecane anchoring groups in DNA attachment to liposomes.
  • To establish structure-activity relationships between anchoring strength, DNA dissociation, and biological properties.

Main Methods:

  • Systematic study of dodecane anchoring groups of varying sizes to create a library of SNA structures.
  • In vitro and in vivo immune stimulation analyses.
  • Evaluation of therapeutic vaccine efficacy in a tumor model and T cell response against viral targets.

Main Results:

  • The most stable dodecane anchor, (C12)9, quadrupled immune stimulation compared to cholesterol-anchored SNAs.
  • Therapeutic vaccination with (C12)9 SNA-encapsulated antigen resulted in 50% survival and complete rechallenge survival in a tumor model.
  • (C12)9 SNA targeting SARS-CoV-2 induced robust T cell responses, effectively killing peptide-pulsed and spike protein-expressing target cells.

Conclusions:

  • Optimizing anchor chemistry is vital for enhancing SNA stability and potency.
  • The (C12)9 SNA demonstrates superior immunotherapeutic potential for cancer and infectious diseases.
  • This approach offers a safer alternative to conventional immunostimulatory DNA, avoiding cytokine storms.