Hyaluronic acid, a naturally occurring mucopolysaccharide, has the ability to target CD44 _ a specific receptor frequently overexpressed on several tumor-cell surfaces, including tumor-initiating stem cells. We have synthesized a series of CD44 targeting lipid and polyamine functionalized HA derivatives that can be mixed and matched, forming self-assembled nanosystems for efficient encapsulation of small molecule drugs, oligonucleotides and small interfering RNAs (siRNAs). 5-40% lipid modification of several HA derivatives was achieved and determined by 1H NMR spectroscopy. The particles size of the HA-nanosystems ranged from ~100-300 nm and the charge after siRNA/drug entrapment was close to neutral as determined by DLS. Several HA-lipid derivatives were able to complex siRNAs as observed by gel retardation assays. Many lipid-modified derivatives formed stable nanoparticles in solution and could encapsulate drugs such as doxorubicin, idarub icin, paclitaxel and cisplatin. Cy3-labeled siRNA was efficiently transfected by HA-lipid derivatives into tumor cells overexpressing CD44 receptors. More interestingly, time dependent tumor uptake was clearly visualized by HA nanoparticels loaded with ICG in mice bearing lung cancers overexpressing CD44 receptors. In addition the siRNA encapsulated HA nanosystems demonstrated tumor selective uptake and target specific gene knock down in vitro and in vivo in solid tumors as well as in metastatic tumors.By judicious selection of the polymer/lipid chain length, charge, degree of modification, molecular weight, and other pertinent variables, the HA based functional macrostructures can be tailored to encapsulate various types of drug and gene payloads and selectively targeted to tumor cells and metastatic lesions efficiently, warranting further evaluations.