The in vivo delivery of nanomedicine is severely hampered by the limited enhanced permeability and retention effect (EPR) in tumors. Aiming at overcoming this limitation and achieving high anti-tumor effect of chemotherapeutics, we specially addressed an available strategy from a viewpoint of increasing the drug loading of nano-carriers. Here, we constructed a novel pH-responsive polymersome based on the drug-driven self-assembly of amphiphilic polyphosphazenes PAP containing the ortho ester group ABD and mPEG2000. Due to the non-covalent attractive forces between PAP and doxorubicin hydrochloride (DOX·HCl), DOX·HCl can induce the self-assembly of PAP via embedding itself in the lamella to form vesicles and the subsequent location in the center aqueous chamber of the resultant nano-vesicles, which resulted in the high drug loading content of 35.77 wt%. In addition, with the incorporation of cholesteryl hemisuccinate (CholHS), the premature leakage of DOX·HCl was significantly inhibited under physiological conditions. Meanwhile, the pH-sensitive drug release occurred at pH 5.5 by the advantage of the pH-sensitive biodegradation of ABD in PAP. Consequently, this CholHS-incorporated DOX·HCl-driven PAP vesicle achieved excellent anti-tumor effect with tumor growth inhibition up to 82.4% in S180 tumor-bearing mice. Taken together, our newly developed drug-driven vesicles may promote the development of efficient drug delivery systems for application in cancer therapy.