PLGA-based nanomedicines have enormous potential for targeted cancer therapy. To boost their stability, targetability, and intracellular drug release, here we developed novel multifunctional PLGA anticancer nanomedicines by combining a reductively cleavable surfactant (RCS), vitamin E-SS-oligo(methyl diglycol l-glutamate), with covalent hyaluronic acid (HA) coating. Reduction-sensitive HA-coated PLGA nanoparticles (rHPNPs) were obtained with small sizes of 55-61 nm and ζ potentials of -26.7 to -28.8 mV at 18.4-40.3 wt % RSC. rHPNPs were stable against dilution and 10% FBS while destabilized under reductive condition. The release studies revealed significantly accelerated docetaxel (DTX) release in the presence of 10 mM glutathione. DTX-rHPNPs exhibited potent and specific antitumor effect to CD44 + A549 lung cancer cells (IC = 0.52 μg DTX equiv/mL). The in vivo studies demonstrated that DTX-rHPNPs had an extended circulation time and greatly enhanced tolerance in mice. Strikingly, DTX-rHPNPs completely inhibited growth of orthotopic human A549-Luc lung tumor in mice, leading to a significantly improved survival rate and reduced adverse effect as compared to free DTX. This study highlights that advanced nanomedicines can be rationally designed by combining functional surfactants and surface coating.