Breast cancer remains one of the most common cancers for females. Drug delivery based on cancer nanotechnology could improve the performance of some chemotherapeutic medicines already used in clinic. The emergence of polymersomes provided the potential to encapsulate hydrophobic/hydrophilic drugs. By modifying the weight ratio of methoxy-poly (ethylene glycol) (mPEG) chain to ethyl-p-aminobenzoate (EAB) side group, a series of amphiphilic graft polyphosphazenes (PEPs) was prepared. PEP can be tuned from micelles to polymersomes with the decrease of mPEG content via dialysis. Either hydrophilic doxorubicin hydrochloride (DOX·HCl) or hydrophobic doxorubicin base (DOX) could be encapsulated into PEP polymersomes with high payload and high encapsulation efficiency due to the strong intermolecular interaction with PEP. Compared with free DOX·HCl administration, in vivo investigation in growth inhibition of MCF-7 xenograft tumors in nude mice demonstrated that PEP polymersomes could enhance life safety without compromise of therapeutic efficacy, especially DOX·HCl loaded delivery system.In this preclinical study, polymerosomes based on PEPs were investigated as doxorubicin delivery systems, demonstrating similar efficacy but less toxicity compared to standard delivery methods.