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Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants
Melissa C. Hanson, … , Stefanie Mueller, Darrell J. Irvine
Melissa C. Hanson, … , Stefanie Mueller, Darrell J. Irvine
Published May 4, 2015
Citation Information: J Clin Invest. 2015;125(6):2532-2546. https://doi.org/10.1172/JCI79915.
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Technical Advance Immunology Article has an altmetric score of 12

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

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Abstract

Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.

Authors

Melissa C. Hanson, Monica P. Crespo, Wuhbet Abraham, Kelly D. Moynihan, Gregory L. Szeto, Stephanie H. Chen, Mariane B. Melo, Stefanie Mueller, Darrell J. Irvine

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Figure 1

NP-cdGMP enhances LN uptake of CDNs.

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NP-cdGMP enhances LN uptake of CDNs.
(A) Groups of BALB/c mice were inje...
(A) Groups of BALB/c mice were injected with cdGMPDY547. The presence of CDN in dLNs (2 μg cdGMPDY547 per mouse, n = 3 per group) and sera of these animals (5 μg cdGMPDY547 per mouse, n = 5 per group) was traced by fluorescence spectroscopy. (B) Representative flow cytometry plots of CDN fluorescence in APCs 24 hours following s.c. injection of 2 μg cdGMPDY547 or NP-cdGMPDY547. (C) Mean percentages of cdGMPDY547+ APCs in inguinal or axillary LNs at 24 hours after immunization of NP-cdGMPDY547 or soluble cdGMPDY547 (n = 3 per group). *P < 0.05, ANOVA followed by Tukey’s multiple comparison test. (D) Kinetics of cdGMPDY547 release from nanoparticles incubated in PBS containing 10% serum at 37°C. (E) Representative images of DC2.4 cells after 2-hour incubations with NP-cdGMPDY547 or soluble cdGMPDY547. Scale bar: 50 μm. (F) Percentage OVAAF647+ DCs over time following injection of NP-cdGMP and NP-OVAAF647 (n = 4 per group).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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