The design of nanodelivery systems has been recently considered as a solution to the major challenge in pharmaceutical research - poor bioavailability of lipophilic drugs. Nanocapsules with liquid oil cores and shells based on amphiphilic polysaccharides were developed here as robust carriers of hydrophobic active compounds. A series of modified charged hyaluronates were synthesized and used as stabilizing shells ensuring also the biocompatibility of the nanocapsules that is crucial for applications related to the delivery of lipophilic drugs in vivo. Importantly, the oil nanodroplets were found to be stably suspended in water for at least 15 months without addition of low molar mass surfactants. Moreover, their size and stability may be tuned by varying the relative content of hydrophobic and hydrophilic groups in the hyaluronate derivatives as was confirmed by dynamic light scattering and nanoparticle tracking analysis as well as electron microscopy. In vivo studies demonstrated that hyaluronate-based nanocapsules accumulated preferentially in the liver as well as in the lungs. Moreover, their accumulation was dramatically potentiated in endotoxemic mice. In vitro studies showed that the nanocapsules were taken up by liver sinusoidal endothelial cells and by mouse lung vascular endothelial cells. Importantly, the capsules were found to be nontoxic in an acute oral toxicity experiment even at a dose of 2000 mg per kg b.w. Biocompatible hyaluronate-based nanocapsules with liquid cores described herein represent a promising and tunable nanodelivery system for lipophilic active compounds via both oral and intravenous administration.