Nanoparticle vaccine delivery platforms are a promising technology for enhancing vaccine immunogenicity. Protein nanoparticles (PNPs), made entirely from antigen, have been shown to induce protective immune responses against influenza. However, the fundamental mechanisms by which PNPs enhance component protein immunogenicity are not understood. Here, we investigate the role of size and coating of model ovalbumin (OVA) PNPs on particle uptake and trafficking, as well as on inflammation and maturation factor expression in dendritic cells (DCs) in vitro. OVA PNPs enhance antigen uptake in a size-independent manner, and experience attenuated endosomal acidification as compared to soluble OVA. OVA PNPs also trigger Fc receptor upregulation. Expression of cytokines IL-1β and TNF-α were PNP size- and coating-dependent, with small (~270 nm) nanoparticles triggering greater inflammatory cytokine production than large (~560 nm) particles. IL-1β expression by DCs in response to PNP stimulation implies activation of the inflammasome, a pathway known to be activated by certain types of nanoparticulate adjuvants. The attenuated acidification and pro-inflammatory profile generated by PNPs in DCs demonstrate that physical biomaterial properties can modulate dendritic cell-mediated antigen processing and adjuvancy. In addition to nanoparticles’ enhancement of DC antigen uptake, our work suggests that vaccine nanoparticle size and coating are uptake-independent modulators of immunogenicity.