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Biomaterials. 2016 Aug;97:85-96. doi: 10.1016/j.biomaterials.2016.03.039. Epub 2016 Apr 1.

Artificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy.

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  • 1Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
  • 2Department of Molecular and Cellular Physiology, Yale University, New Haven, CT 06520, USA.
  • 3Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Department of Chemical and Environmental Engineering, Yale University, New Haven, CT 06520, USA; Department of Immunobiology, Yale University, New Haven, CT 06520, USA. Electronic address:


Antigen-presenting cells (APCs) sense microorganisms via pathogen-associated molecular patterns (PAMPs) by both extra- and intracellular Toll-like Receptors (TLRs), initiating immune responses against invading pathogens. Bacterial PAMPs include extracellular lipopolysaccharides and intracellular unmethylated CpG-rich oligodeoxynucleotides (CpG). We hypothesized that a biomimetic approach involving antigen-loaded nanoparticles (NP) displaying Monophosphoryl Lipid A (MPLA) and encapsulating CpG may function as an effective "artificial bacterial" biomimetic vaccine platform. This hypothesis was tested in vitro and in vivo using NP assembled from biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer, surface-modified with MPLA, and loaded with CpG and model antigen Ovalbumin (OVA). First, CpG potency, characterized by cytokine profiles, titers, and antigen-specific T cell responses, was enhanced when CpG was encapsulated in NP compared to equivalent concentrations of surface-presented CpG, highlighting the importance of biomimetic presentation of PAMPs. Second, NP synergized surface-bound MPLA with encapsulated CpG in vitro and in vivo, inducing greater pro-inflammatory, antigen-specific T helper 1 (Th1)-skewed cellular and antibody-mediated responses compared to single PAMPs or soluble PAMP combinations. Importantly, NP co-presentation of CpG and MPLA was critical for CD8(+) T cell responses, as vaccination with a mixture of NP presenting either CpG or MPLA failed to induce cellular immunity. This work demonstrates a rational methodology for combining TLR ligands in a context-dependent manner for synergistic nanoparticulate vaccines.


Biomimetic; Cellular immunity; Nanoparticle; PAMP; TLR; Vaccine

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