Duality Vaccination through Nanodesign of Click-Ligated B-Cell Inhibitory Receptor Bridging
Abstract
Synthesis of precise and robust molecular architectures is critical to harness the power of the immune system. The dimensions, rigidity and multivalency of nanoparticles contribute to eliciting high levels of antibodies from vaccination. However, antibodies vary hugely in quality: some antibodies are highly effective at neutralizing pathogens, while others provide little or no benefit. Here we establish switchable and modular platforms for protein and nanoparticle assembly that program the target of antibody responses. We introduce Duality vaccination: the simultaneous delivery of activating and inhibitory stimuli for focusing immune responses. To construct activatory immunogens, we employ click biology with spontaneous amidation to functionalize plug-and-display self-assembling porous dodecahedral nanocages. We construct inhibitory immunogens using SpyMask protease-gated bispecific assembly, ligating the antigen to binders that bridge the B cell receptor to immune checkpoint receptors. This dual immunogen architecture tailors the elicited antibodies to down-modulate undesired B cell responses. We establish the effect of temporal and spatial separation of activatory and inhibitory immunogen delivery. We further explore sensitivity to valency, linker flexibility and adjuvant delivery, employing model targets and coronavirus antigens. Dual programmable functionalization identifies key nanodesign features to control in vivo outputs, providing logic-gating towards urgent challenges in the creation of protective vaccines.
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BibTeX
@misc{admans2026duality,
title = {{Duality Vaccination through Nanodesign of Click-Ligated B-Cell Inhibitory Receptor Bridging}},
author = {Gabrielle Admans and Rory A. Hills and Diana Melnyk and Alexander A. Cohen and Claudia L. Driscoll and Mark S. Cragg and Pamela J. Bjorkman and Tiong Kit Tan and Mark R. Howarth},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762652},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762652v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Duality Vaccination through Nanodesign of Click-Ligated B-Cell Inhibitory Receptor Bridging
AU - Gabrielle Admans
AU - Rory A. Hills
AU - Diana Melnyk
AU - Alexander A. Cohen
AU - Claudia L. Driscoll
AU - Mark S. Cragg
AU - Pamela J. Bjorkman
AU - Tiong Kit Tan
AU - Mark R. Howarth
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762652
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762652v1
AB - Synthesis of precise and robust molecular architectures is critical to harness the power of the immune system. The dimensions, rigidity and multivalency of nanoparticles contribute to eliciting high levels of antibodies from vaccination. However, antibodies vary hugely in quality: some antibodies are highly effective at neutralizing pathogens, while others provide little or no benefit. Here we establish switchable and modular platforms for protein and nanoparticle assembly that program the target of antibody responses. We introduce Duality vaccination: the simultaneous delivery of activating and inhibitory stimuli for focusing immune responses. To construct activatory immunogens, we employ click biology with spontaneous amidation to functionalize plug-and-display self-assembling porous dodecahedral nanocages. We construct inhibitory immunogens using SpyMask protease-gated bispecific assembly, ligating the antigen to binders that bridge the B cell receptor to immune checkpoint receptors. This dual immunogen architecture tailors the elicited antibodies to down-modulate undesired B cell responses. We establish the effect of temporal and spatial separation of activatory and inhibitory immunogen delivery. We further explore sensitivity to valency, linker flexibility and adjuvant delivery, employing model targets and coronavirus antigens. Dual programmable functionalization identifies key nanodesign features to control in vivo outputs, providing logic-gating towards urgent challenges in the creation of protective vaccines.
SN - 2692-8205
ER -