ArticlebioRxiv : the preprint server for biology2026
Spatiotemporal control of STING activation and saRNA delivery decouples humoral and cellular immunity.
Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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15 authors.
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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
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