Management of glioblastoma multiforme (GBM), a cerebral glioma with highest-grade malignancy, is a crucial challenge to current anticancer treatment because the lack of GBM-targeting capability of antitumor drug, such as carmustine (BCNU) with a short half-life, along with low blood-brain barrier (BBB) permeability to achieve the clinical efficacy. Hence, polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticles comprising stable core-shell structure with tamoxifen were crosslinked with sialic acid (SA-TAM-PEI-PLGA NPs) as nanocarriers to improve bioavailability of BCNU for pharmacotherapy. The brain-targeted experiments revealed that an increasing SA level improved BBB permeability for BCNU, and was associated with a reduction in transendothelial electrical resistance and an increase in propidium iodide penetration of endothelial monolayer. Immunocytochemical staining images evidenced that surface SA was critical in triggering transcytosis through N-acetylglucosamine on human cerebral microvessel endothelia, and surface crosslinking restrained macrophage phagocytosis. A high TAM level on the carrier surface reduced the survival rate of human U87, and western blots showed that conjugated TAM induced apoptosis of the cancer cells. The use of SA-TAM-PEI-PLGA NPs carrying BCNU as a pharmaceutical preparation is an effective strategy to overcome the BBB restriction and activate apoptosis of tumor cells to prevent the proliferation of GBM. © 2020 Taiwan Institute of Chemical Engineers