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PreprintCC BYbioRxiv

Spatiotemporal control of STING activation and saRNA delivery decouples humoral and cellular immunity

  • D. J. Peeler1
  • Z. Wang
  • L. Spiga
  • S. Jokonya
  • C. Thomas
  • D. Reumann
  • K. Shramko
  • L. Rigat Nogareda
  • P. F. McKay
  • D. C. Nguyen
  • M. Briones Orta
  • P. S. Stayton
3 more authors
  • M. M. Stevens
  • R. J. Shattock
  • J. S. Tregoning
  1. 1Department of Materials, Department of Bioengineering and Institute for Biomedical Engineering, Imperial College London, UK; Department of Infectious Disease, I
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Abstract

Self-amplifying mRNA (saRNA) vaccine formulations link the location and timing of antigen expression to innate immune stimulation by both RNA cargo and carrier. We hypothesized that targeting a polymeric STING agonist prodrug (polySTING) to antigen-presenting cells (APCs) independently of saRNA delivery could tune vaccines responses without limiting saRNA expression. By varying the time and location of STING signaling relative to saRNA delivered by muscle-restricted (polyplex, PP) and lymph node-draining (lipid nanoparticle, LNP) saRNA formulations, we studied how spatiotemporal colocalization of type I interferon (IFN-I) and antigen expression impacts innate and adaptive vaccine responses. Co-administering PP + polySTING decreased antigen-specific adaptive type 1 responses by mismatching early lymph node IFN-I and later arriving antigen; this could be reversed by delaying polySTING delivery timing. Conversely, synchronizing early LNP saRNA delivery and polySTING IFN-I in the lymph node boosted saRNA type 1 T cell responses without impacting humoral immunity, which re-directed antigen-intrinsic immune skewing and enhanced protection against pulmonary Acinetobacter baumannii challenge. Collectively, these findings define formulation-specific innate immune responses to saRNA vaccines and establish APC-targeted adjuvants as a strategy to tune saRNA vaccine immunogenicity.

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Cite

BibTeXRIS
BibTeX
@misc{peeler2026spatiotemporal,
  title = {{Spatiotemporal control of STING activation and saRNA delivery decouples humoral and cellular immunity}},
  author = {D. J. Peeler and Z. Wang and L. Spiga and S. Jokonya and C. Thomas and D. Reumann and K. Shramko and L. Rigat Nogareda and P. F. McKay and D. C. Nguyen and M. Briones Orta and P. S. Stayton and M. M. Stevens and R. J. Shattock and J. S. Tregoning},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.11.751026},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.11.751026v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Spatiotemporal control of STING activation and saRNA delivery decouples humoral and cellular immunity
AU  - D. J. Peeler
AU  - Z. Wang
AU  - L. Spiga
AU  - S. Jokonya
AU  - C. Thomas
AU  - D. Reumann
AU  - K. Shramko
AU  - L. Rigat Nogareda
AU  - P. F. McKay
AU  - D. C. Nguyen
AU  - M. Briones Orta
AU  - P. S. Stayton
AU  - M. M. Stevens
AU  - R. J. Shattock
AU  - J. S. Tregoning
PY  - 2026
DA  - 2026/09/11
PB  - bioRxiv
DO  - 10.64898/2026.09.11.751026
UR  - https://www.biorxiv.org/content/10.64898/2026.09.11.751026v1
AB  - Self-amplifying mRNA (saRNA) vaccine formulations link the location and timing of antigen expression to innate immune stimulation by both RNA cargo and carrier. We hypothesized that targeting a polymeric STING agonist prodrug (polySTING) to antigen-presenting cells (APCs) independently of saRNA delivery could tune vaccines responses without limiting saRNA expression. By varying the time and location of STING signaling relative to saRNA delivered by muscle-restricted (polyplex, PP) and lymph node-draining (lipid nanoparticle, LNP) saRNA formulations, we studied how spatiotemporal colocalization of type I interferon (IFN-I) and antigen expression impacts innate and adaptive vaccine responses. Co-administering PP + polySTING decreased antigen-specific adaptive type 1 responses by mismatching early lymph node IFN-I and later arriving antigen; this could be reversed by delaying polySTING delivery timing. Conversely, synchronizing early LNP saRNA delivery and polySTING IFN-I in the lymph node boosted saRNA type 1 T cell responses without impacting humoral immunity, which re-directed antigen-intrinsic immune skewing and enhanced protection against pulmonary Acinetobacter baumannii challenge. Collectively, these findings define formulation-specific innate immune responses to saRNA vaccines and establish APC-targeted adjuvants as a strategy to tune saRNA vaccine immunogenicity.
ER  -