In this work, we developed a novel core/shell chitosan (Cs)/hyaluronan (HA)-based hybrid nanoparticle, i.e. SNX@Cs-SNX/cHA, with good stability in the bloodstream and intracellular environment-sensitive drug delivery for breast cancer therapy. The core was a drug-loaded self-assembled micelle (SNX@Cs-SNX), and the shell was crosslinked to cysteine-conjugated hyaluronan (cHA) by disulfide bonds. Thanks to the combination of chemical bonding and physical encapsulation, the drug loading capacity of SNX@Cs-SNX/cHA nanoparticles was up to (14.6 ± 0.3)% in mass percentage. These stabilized core/shell nanoparticles were little affected by ionic strength (0.05-1.0 M sodium chloride solution), pH (6.8 and 7.4) and human plasma mimicking the bloodstream, but promptly disassembled by the multi-stimuli of glutathione (GSH), hyaluronidases (Hyals) and acidity (pH 5.0) mimicking the intracellular environment of breast cancer cells. In vitro 84% of the loaded drugs was released by GSH/Hyals/pH multi-stimuli within 72 h, as opposed to 28% at pH 7.4. SNX@Cs-SNX/cHA nanoparticles were highly endocytosed by both MCF-7 and MDA-MB-453 breast cancer cells and escaped from the endosomes/lysosomes as revealed by confocal laser scanning microscopy, showing a close IC50 value of 24.5 ng mL-1 and 41.0 ng mL-1 respectively to pure SNX. Thus, the SNX@Cs-SNX/cHA nanoparticle, which can not only increase the drug loading ability and stability in the blood circulation, but also control the fast intracellular drug delivery by GSH/Hyals/pH multi-stimuli in breast cancer cells, is a potential drug carrier for breast cancer therapy.