Curcuminoid (Cur) loaded polysaccharide nanoformulations with blood-brain barrier (BBB) penetration and brain targeting properties, based on hyaluronic acid (HA) and chitosan hydrochloride (CSH) (Lf-Cur-PSNPs) were developed as a novel delivery system for malignant glioma. Formulations were investigated for physicochemical characteristics, cytotoxicity, uptake, and BBB penetration. The results showed that Lf-Cur-PSNPs (concentration of Lf was 0.5mg/mL) were preferentially taken up by brain capillary endothelial cells than Cur-PSNPs at any time. After crossing the BBB, Lf-Cur-PSNPs remained largely intact and were more effective in targeting glioma cells (C6). In vivo imaging studies in mice exposed Lf-PSNPs could effectively permeate BBB and preferentially accumulate in the brain (2.39 times greater than PSNPs). Moreover, PSNPs were detected in brain up to 72h. This data indicates that Lf-Cur-PSNPs could effectively target and accumulate within the gliomas after enhanced permeation through BBB, thus should be further explored for their potential in CNS maliganancies.