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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
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Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer

Daniel Shae1, Kyle W Becker1, Plamen Christov2

  • 1Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.

Nature Nanotechnology
|January 22, 2019
PubMed

Insights

Novel STING-activating nanoparticles (STING-NPs) improve the delivery of cyclic dinucleotides (CDNs) like cGAMP. These nanoparticles enhance anti-tumour immunity and therapeutic outcomes in preclinical models.

Area of Science:

  • Immunology
  • Nanotechnology
  • Drug Delivery

Background:

  • Cyclic dinucleotide (CDN) agonists targeting stimulator of interferon genes (STING) show promise as immunotherapeutics.
  • Current CDN efficacy is limited by poor cellular delivery and rapid clearance, hindering STING activation in the cytosol.

Purpose of the Study:

  • To develop rationally designed polymersomes, termed STING-activating nanoparticles (STING-NPs), for enhanced cytosolic delivery of 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP).
  • To evaluate the therapeutic potential of STING-NPs in converting immunosuppressive tumors into immunogenic, tumoricidal microenvironments.

Main Methods:

  • STING-NPs were engineered as polymersomes encapsulating the endogenous STING ligand, cGAMP.
  • The biological potency, STING signaling, and anti-tumor effects of STING-NPs were assessed in preclinical models.
  • Efficacy was evaluated in freshly isolated human melanoma tissue.

Main Results:

  • STING-NPs significantly enhanced the biological potency of cGAMP and improved STING signaling in the tumor microenvironment and sentinel lymph nodes.
  • Treatment with STING-NPs converted immunosuppressive tumors to immunogenic, tumoricidal microenvironments, inhibiting tumor growth.
  • STING-NPs improved responses to immune checkpoint blockade, induced long-term survival, and generated protective immunological memory.

Conclusions:

  • STING-NPs represent a promising nanotechnology for improving CDN delivery and enhancing cancer immunotherapy.
  • These nanoparticles demonstrate potential for improving clinical outcomes in cancer patients, including those with melanoma.

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