To date, improving oral bioavailability of water-soluble drugs with poor membrane permeability is still challenging. An example of this includes doxorubicin hydrochloride (DOX center dot HCl), a widely used chemotherapeutic. We therefore developed a novel DOX center dot HCl-loaded polymersome (Ps-DOX center dot HCl) self-assembled by amphiphilic beta-cyclodextrin-centered triarm star polymer (mPEG(2k)-PLA(3k))(3)-CD with the considerable drug loading capability. Using Madin-Darby canine kidney (MDCK) cells trans-well models, it was found that the cellular uptake and absorptive transport of DOX center dot HCl was significantly increased and the efflux was attenuated when delivered through polymersomes than free drugs. This phenomenon was further verified in mechanistic studies, which was attributed to the change in membrane transport pathway from paracellular route (free DOX center dot HCl) to active transcellular transport (drug-loaded polymersomes). Moreover, in vivo, pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX center dot HCI compared with free DOX center dot HCl (7.32-fold), as well as extended half-life (8.22-fold). This resulted in a substantial anticancer efficacy against mouse sarcoma 180 (S180) tumor in vivo. The cardiotoxicity, which is intrinsically induced by DOX center dot HCl, and toxicity toward gastrointestinal tissues were avoided according to histological studies. These findings indicate that (mPEG(2k)-PLA(3k))(3)-CD copolymer displays great potential as a vehicle for the effective oral delivery of water-soluble drugs with low permeability.