Reduction-responsive shell-sheddable micelles based on disulfide-linked chondroitin sulfate-cholesterol conjugates (CS-ss-Chol) were developed for efficient encapsulation and triggered intracellular release of hydrophobic drug. CS-ss-Chol conjugates with different cholesterol content were synthesized and self-assembled into spherical micelles in aqueous medium with tunable sizes (124-237 nm) and desirable critical micelle concentration (CMC) (5.8-3.6 x 10(-2) mg/L). These micelles were highly sensitive to intracellular reductive environments, which resulted in fast formation of large aggregates due to shedding of the CS shells through reductive cleavage of the intermediate disulfide bonds. Quercetin, a model hydrophobic drug, was efficiently loaded into the core of these micelles, with a drug loading efficiency of 23.4%. The in vitro release studies showed that quercetin release was minimal (<20% in 24 h) at low concentrations of dithiothreitol (DTT, 10 mu M) mimicking the extracellular environment, but significantly enhanced (>50% in 24 h) under tumor-relevant reductive condition (DTT, 20 mM). MTT assays against HeLa cells and HSF cells indicated that these CS-ss-Chol micelles had negligible toxicity up to a conjugate concentration of 200 mu g/mL. These reduction-responsive shell-sheddable micelles may offer a promising and generic means to intracellularly delivery a wide variety of hydrophobic payloads in a selective and tunable way. Published by Elsevier B.V.