This current study employed pH-and GSH-sensitive copolymers to prepare nanocarriers for targeted and efficient drug delivery. The nanocarriers were constructed by a family of dual pH-and GSH-responsive copolymers synthesized from poly(ethylene glycol) (PEG), 2,2'-dithiodiethanol (DiT), N-methyldiethanolamine (MDEA) and hexamethylene diisocyanate (HDI). As a commonly used targeting ligand, hyaluronic acid (HA) chains were found to be semi-interpenetrated into the surface of the nanocarriers. Results from these studies demonstrated that the DOX-loaded dual stimuli-responsive nanocarriers with HA modification exhibited excellent tumor targeting, successful cell intake, and anti-cancer activity with minimal systemic toxicity. The DOX-loaded dual stimuli-responsive nanocarriers have special potential for targeted therapy against CD44-expressing tumor.