Nanocarriers for Cytoplasmic Delivery: Cellular Uptake and Intracellular Fate of Chitosan and Hyaluronic Acid-Coated Chitosan Nanoparticles in a Phagocytic Cell Model

The cellular uptake of hyaluronic‐acid‐coated, negatively charged chitosan/triphosphate nanoparticles and that of uncoated, positively charged ones is investigated by studying cellular localization, uptake kinetics and mechanism of internalization in J774.2 macrophages, using non‐phagocytic L929 fibroblasts as a control for uncoated nanoparticles. Both kinds of nanoparticles undergo endosomal escape and adopt a similar clathrin‐based endocytic mechanism. The surface decoration with HA profoundly influences the kinetics of cellular uptake, with an at least two orders of magnitude slower kinetics, but also the nature of the binding on the cellular surface. The endocytosis of chitosan nanoparticles (green) with and without hyaluronic acid‐coating is studied in murine macrophages. Both coated and uncoated nanoparticles evade endolysosomal compartments (red), but the hyaluronic acid coating controls stability in media, cellular interactions and uptake kinetics.