The selective targeting of dendritic cells (DCs) can lead to more efficacious vaccines. Here, materials have been designed for a synergic DC targeting: interacting with CD44 through the use of hyaluronic acid (HA), and with mannose-binding lectins (typical DC pattern recognition receptors) through HA mannosylation. Negatively charged, HA-displaying nanoparticles are produced via polyelectrolyte complexation of (mannosylated) HA and high- or low- molecular-weight chitosan (CS, 36 and 656 kDa). Using CS36, HA is better exposed and the particles have a higher affinity for HA receptors; this means a higher number of receptors clustered around each particle and, due to the rather limited CD44 availability, an overall lower uptake per cell. Employing Langerhans-like XS106 cells, all particles show negligible toxicity or inflammatory activation. The cellular uptake kinetics are qualitatively similar to other leukocytic models and thus considered to be CD44-dominated; the uptake increases with increasing HA mannosylation and with the use of adjuvants (LPS, mannan) for CS36/HA but not for CS656//HA particles; this indicates that the interactions with mannose-binding receptors requires a correct ligand presentation, and only in that case can they be enhanced by appropriate adjuvants. In summary, mannose-binding receptors can be used to enhance the internalization of HA-based carriers, although this positive synergy depends on the mode of ligand presentation.