Breast cancer is the most common malignancy and the second leading cause of death among women in the United States. The commonly used breast cancer treatment strategies include surgery, chemotherapy, radiation, and hormonal therapy. Since chemotherapeutic agents do not adequately differentiate between normal and cancerous cells, systemic toxicity and adverse effects associated with these anticancer drugs limit their therapeutic efficacy. In addition, uncontrolled cell proliferation and insufficient blood supply produce low oxygen partial pressure or hypoxia in almost all solid tumors. Hypoxia increases cancer cell survival through aggressiveness, metastasis, and resistance to chemotherapy, leading to poor clinical outcomes. Targeted drug delivery nanoparticles can significantly reduce off-target toxicity of chemotherapy by selectively targeting tumor tissues. Polymersomes are self-assembled drug-encapsulated polymeric nanoparticles in which an aqueous core is enclosed by a bilayer membrane. To attain the appropriate therapeutic efficacy, polymersomes need to rapidly release their anticancer drug at the tumor sites. To fulfill this requirement, stimuli-responsive polymersomes have been developed. Since most of the tumors have hypoxic areas inside, hypoxia-responsive polymersomes are one of the most effective drug delivery vehicles for cancer treatment. To prepare targeted drug delivery systems, functionalizing polymersomes with specific ligands intended to be recognized by the receptors of the cancer cells, is the most common strategy. Herein, we designed three distinct hypoxia-responsive polymersomes for targeting breast cancer tissues. More than 80% of breast cancers express estrogen receptor (ER-positive), and about 15-25% of them do not express any receptors (triple-negative). Hence, we decorated our polymersomes with three different ligands including estradiol and endoxifen for targeting ER-positive breast microtumors, and iRGD peptide for targeting triple-negative breast tumors.