Objective To prepare an angiopep-2 modified disulfide cross-linked lipoic acid-polyarginine polypeptide and histidine nanomicelle loading anticancer agent doxorubicin (DOX) brain-targeting drug delivery system for glioma (LHRss-An/DOX). Methods LHRss-An/DOX was prepared by ultrasonic emulsification method, and the particle size, zeta potential and appearance were detected. The loading content (LC) and encapsulation efficiency (EE) of DOX in the polymeric micelles and the in vitro release profiles were determined. Transmembrane transport efficiency of LHRss-An/DOX was evaluated using in vitro blood-brain barrier (BBB) model. The intracellular distribution of DOX and glioma targeting ability were observed by laser scanning confocal microscopy. Results Spherical micelles LHRss-An/DOX were successfully obtained. The mean particle size of the LHRss-An/DOX was (100.9±8.7) nm, polymer dispersity index was 0.232, zeta potential was (28.8±3.3) mV, optimal drug loading ratio was 40%, LC was 15.8% and EE was 55.3%. Cumulative DOX release within 72 h reached (60.3±2.6)%, (84.1±3.9)% and (96.6±2.7)% in the solutions of pH 7.4, pH 5.5 and pH 5.5 with 10 mmol/L DL-dithiothreitol (DTT), respectively. The transporting BBB efficiency of LHRss-An/DOX was 2.04 and 4.27 times of that of LHRss/DOX and free DOX, respectively (both P<0.05). The fluorescence intensity of LHRss-An/DOX uptake by of glioma cells U251 was stronger than that of LHRss/DOX and free DOX. Conclusion Angiopep-2-modified loading drug nanomicelles have good penertrating capacity of BBB and glioma-targeting, and it can be a potential drug delivery system for brain-targeting.