Rationally designed tunable amphiphilic glycopolymers for safe and effective vaccine adjuvanticity
- 1Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina 4012 Marsico Hall, 125 Mason Farm Road Chapel Hill NC USA
- 2Joint Department of Biomedical Engineering, University of North Carolina Chapel Hill NC USA
- 3Department of Microbiology and Immunology, School of Medicine, UNC Chapel Hill NC USA
Abstract
Vaccine adjuvants require specific molecular cues to effectively replicate pathogen-derived immunostimulatory signals. Among these, carbohydrate-lipid motifs found on the mycobacterial cell wall are particularly potent targets, as they engage C-type lectin receptors (CLRs) to drive specific Th1/Th17-skewed immunity. To explore this potential, amphiphilic glycopolymers integrating trehalose and long-chain lipid motifs were synthesized to investigate how the covalent co-display of carbohydrate and lipid cues modulates polymer self-assembly and immune activation. By deconstructing the CLR agonist trehalose-6,6′-dibehenate (TDB) into trehalose and behenyl methacrylate monomers, we created a modular platform that overcomes the hydrophobicity and fixed stoichiometry of the parent glycolipid. This strategy presents carbohydrate and lipid signals in close molecular proximity on a single polymer scaffold. A series of well-defined random copolymers comprising trehalose methacrylate and behenyl methacrylate were prepared via reversible addition–fragmentation chain-transfer (RAFT) polymerization, affording polymers with controlled molecular weights (Mn ≈ 29–32 kDa) and tunable lipid incorporation (0–40 mol%). Adjustment of the trehalose-to-lipid feed ratio (T : B = 300 : 0 to 180 : 120) provided precise control over amphiphilicity. Incorporation of hydrophobic behenoyl segments induced spontaneous self-assembly in aqueous media, forming nanoscale micelles with hydrodynamic diameters increasing from approximately 110 to 130 nm as lipid content increased. Polymer amphiphilicity strongly shaped the innate immune activation in vitro, with the 10 mol% lipid copolymer eliciting the highest proinflammatory cytokine response. These findings suggest that covalent co-presentation of trehalose and lipid motifs within a single polymer scaffold enables activation of innate immune pathways.
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BibTeX
@article{hendricksen2026rationally,
title = {{Rationally designed tunable amphiphilic glycopolymers for safe and effective vaccine adjuvanticity}},
author = {Aaron T. Hendricksen and Luis Ontiveros-Padilla and Connor T. Murphy and Grace L. Williamson and Alexandra M. Lopez and Eric M. Bachelder and Kristy M. Ainslie},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra05875b},
url = {https://europepmc.org/article/PMC/PMC13674014},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Rationally designed tunable amphiphilic glycopolymers for safe and effective vaccine adjuvanticity
AU - Aaron T. Hendricksen
AU - Luis Ontiveros-Padilla
AU - Connor T. Murphy
AU - Grace L. Williamson
AU - Alexandra M. Lopez
AU - Eric M. Bachelder
AU - Kristy M. Ainslie
PY - 2026
DA - 2026/10/16
JO - RSC advances
DO - 10.1039/d6ra05875b
UR - https://europepmc.org/article/PMC/PMC13674014
AB - Vaccine adjuvants require specific molecular cues to effectively replicate pathogen-derived immunostimulatory signals. Among these, carbohydrate-lipid motifs found on the mycobacterial cell wall are particularly potent targets, as they engage C-type lectin receptors (CLRs) to drive specific Th1/Th17-skewed immunity. To explore this potential, amphiphilic glycopolymers integrating trehalose and long-chain lipid motifs were synthesized to investigate how the covalent co-display of carbohydrate and lipid cues modulates polymer self-assembly and immune activation. By deconstructing the CLR agonist trehalose-6,6′-dibehenate (TDB) into trehalose and behenyl methacrylate monomers, we created a modular platform that overcomes the hydrophobicity and fixed stoichiometry of the parent glycolipid. This strategy presents carbohydrate and lipid signals in close molecular proximity on a single polymer scaffold. A series of well-defined random copolymers comprising trehalose methacrylate and behenyl methacrylate were prepared via reversible addition–fragmentation chain-transfer (RAFT) polymerization, affording polymers with controlled molecular weights (Mn ≈ 29–32 kDa) and tunable lipid incorporation (0–40 mol%). Adjustment of the trehalose-to-lipid feed ratio (T : B = 300 : 0 to 180 : 120) provided precise control over amphiphilicity. Incorporation of hydrophobic behenoyl segments induced spontaneous self-assembly in aqueous media, forming nanoscale micelles with hydrodynamic diameters increasing from approximately 110 to 130 nm as lipid content increased. Polymer amphiphilicity strongly shaped the innate immune activation in vitro, with the 10 mol% lipid copolymer eliciting the highest proinflammatory cytokine response. These findings suggest that covalent co-presentation of trehalose and lipid motifs within a single polymer scaffold enables activation of innate immune pathways.
SN - 2046-2069
ER -