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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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Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
Department of Molecular and Cellular Physiology, Yale University, New Haven, CT 06520, USA.
Department 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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