We report the synthesis and characterization of a polymeric nanoparticle (NP) based on hyperbranched polyglycerol (HPG) containing a hydrophobic core and a hydrophilic shell, and assessed its suitability to be developed as a systemic anticancer drug carrier. HPG NP displayed low toxicity to primary cell cultures and were well-tolerated in mice after intravenous administration. When tested in mice tumor xenograft models, HPG NP accumulated significantly in the tumors with low accumulation in the liver and the spleen. In vitro studies demonstrated that HPG NP was capable of hydrophobically binding docetaxel and releasing it in a controlled manner. The HPG NP formulation of docetaxel conferred a preferential protective effect on primary non-cancerous cells while effectively killing cancer cells, indicating great potential for widening its therapeutic index. Taken together, these data indicate that HPG NP is a highly promising nanocarrier platform for systemic delivery of anticancer drugs. The use of polyethylene glycol on nano-carriers as "stealth" to deliver intravenous drugs is well known. Here, the authors developed polymeric nanoparticle (NP) with hyperbranched polyglycerol (HPG) and tested its efficacy in delivering docetaxel. The results showed that this formulation could preferentially killed cancer cells with a high therapeutic index. It seems that this platform could have a great potential in cancer therapy.