Targeting dendritic cells with nanoparticles is an attractive modality for instigating immunity or inducing immunosuppression. An important aspect of successful delivery of antigen and immune modulators to these cells is the efficacy of nanoparticle internalization, which can dictate the strength and robustness of immune responses; optimizing particulate uptake is thus key. We compared the internalization of two nanoparticulate platforms: a vesicular “nanogel” platform with a lipid exterior, and the widely-used solid biodegradable poly(lactic-co-glycolic acid) (PLGA) system. We found that nanogels were more effectively internalized by dendritic cells in vitro, as demonstrated by fluorescent tracer measurements. Additionally, the magnitude of dendritic cell immunosuppression achieved by nanogels loaded with mycophenolic acid, an immunosuppressant, was greater than similarly drug-loaded PLGA. Although both types of particles could mitigate the production of inflammatory cytokines and the up-regulation of stimulatory surface markers, nanogels yielded greater reductions. These in vitro measurements correlated with in vivo efficacy, where immunosuppressive therapy with nanogels extended the survival of lupus-prone NZB/W F1 mice whereas PLGA particles did not. Our results highlight the importance of material on nanoparticle uptake by dendritic cells, which impacts the quality of therapeutic immunosuppression.