Mannose-Functionalized “Pathogen-like” Polyanhydride Nanoparticles Target C-Type Lectin Receptors on Dendritic Cells

Targeting pathogen recognition receptors ondendritic cells (DCs) offers the advantage of triggering specificsignaling pathways to induce a tailored and robust immuneresponse. In this work, we describe a novel approach to targetedantigen delivery by decorating the surface of polyanhydridenanoparticles with specific carbohydrates to provide “pathogenlike”properties that ensure nanoparticles engage C-type lectinreceptors on DCs. The surface of polyanhydride nanoparticleswas functionalized by covalent linkage of dimannose and lactoseresidues using an amine carboxylic acid coupling reaction.Coculture of functionalized nanoparticles with bone marrow derivedDCs significantly increased cell surface expression ofMHC II, the T cell costimulatory molecules CD86 and CD40,the C-type lectin receptor CIRE and the mannose receptorCD206 over the nonfunctionalized nanoparticles. Both nonfunctionalizedand functionalized nanoparticles were efficientlyinternalized by DCs, indicating that internalization of functionalizednanoparticles was necessary but not sufficient to activateDCs. Blocking the mannose and CIRE receptors prior to theaddition of functionalized nanoparticles to the culture inhibited the increased surface expression of MHC II, CD40 and CD86.Together, these data indicate that engagement of CIRE and the mannose receptor is a key mechanism by which functionalizednanoparticles activate DCs. These studies provide valuable insights into the rational design of targeted nanovaccine platforms toinduce robust immune responses and improve vaccine efficacy