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Albumin nanoparticles have been increasingly viewed as an effective way of delivering chemotherapeutics to solid tumors. Here, we report the one-pot development of a unique prototype of doxorubicin-loaded nanoparticles (NPs) made of naïve albumin (HSA) plus cationic- (c-HSA) or mannose-modified-albumin (m-HSA), with the goal of traversing the blood–brain barrier and targeting brain tumors. c-HSA was synthesized by conjugating ethylenediamine to naïve HSA. Then, m-HSA was derivatized using mannopyranoside via a thiol-maleimide reaction. The c/m-HSA NPs were prepared using a mixture solution of c- and m-HSAs in deionized water and doxorubicin in ethanol/chloroform in the same pot using a high-pressure homogenizer. The c/m-HSA NPs were spherical and well-dispersed, with a particle size of 90.5 ± 3.1 nm and zeta-potential of − 12.0 ± 0.3 mV at c- and m-HSA feed ratios of 5% and 10%, respectively. The c/m-HSA NPs displayed good stability over 3 days based on particle size and a linear gradual doxorubicin release over 2 days. Specifically, the inhibitory concentration (IC50; 0.5 ± 0.02 μg/ml) of c/m-HSA NPs was > 2.2–15.6 fold lower than those of doxorubicin or the other HSA NPs. Moreover, among HSA NPs, c/m-HSA NPs exhibited the most prominent performances in transport across the bEnd.3 cell monolayer and uptake in bEnd.3 cells as well as U87MG glioblastoma cells and spheroids. Furthermore, c/m-HSA NPs were localized to a greater extent in brain glioma compared to naïve HSA NPs. Orthotopic glioma-bearing mice treated with c/m-HSA NPs displayed significantly smaller tumors than the mice treated with saline, doxorubicin or HSA NPs. This improved anti-glioma efficacy seemed to be due to the dual-enhanced system of dual cationic absorptive transcytosis and glucose-transport by the combined use of c- and m-HSAs. The c/m-HSA NPs have potential as a novel anti-brain cancer agent with good targetability.The doxorubicin-loaded nanoparticles made of naïve-, cationic- and mannose-modified-albumin was facilely fabricated in one-pot and displayed excellent anti-tumor efficacy and targetability in orthotopic glioma-bearing mice.