Carbon nano-onions (CNOs) are promising materials for biomedical applications due to their low cytotoxicity and excellent biocompatibility. Supramolecular functionalization with biocompatible polymers is an effective strategy to develop engineered drug carriers for targeted delivery applications. In this study, we report the use of a hyaluronic acid-phospholipid (HA-DMPE) conjugate to target CD44 overexpressing cancer cells, while enhancing solubility of the nanoconstruct. Non-covalently functionalized CNOs with HA-DMPE show excellent in vitro cell viability in human breast carcinoma cells overexpressing CD44 and are uptaken to a greater extent compared to human ovarian carcinoma cells with an undetectable amount of CD44. In addition, they possess high in vivo biocompatibility in zebrafish (Danio Rerio) during the different stages of development and they prevalently localize in the digestive tract of the zebrafish larvae.