Despite being one of the most potent chemotherapeutics, doxorubicin (DOX) facilitates cardiac toxicity by irreversibly damaging the cardiac muscle as well as severely dysregulating the immune system and impairing the resolution of cardiac inflammation. Herein, we report synthesis and aqueous self-assembly of nanosized polymersomes from temperature-responsive poly(3-methyl-N-vinylcaprolactam)-b/ock-poly(N-vinylpyrrolidone) (PMVC-PVPON) diblock copolymers and demonstrate their potential to minimize DOX cardiotoxicity compared to liposomal DOX. RAFT polymerization of vinylpyrrolidone and 3-methyl-N-vinylcaprolactam, which are structurally similar monomers but have drastically different hydrophobicity, allows decreasing the cloud point of PMVCm-PVPONn copolymers below 20 degrees C. The lower critical solution temperature (LCST) of the PMVC58-PVPONn copolymer varied from 19.2 to 18.6 and to 15.2 degrees C by decreasing the length of the hydrophilic PVPONn block from n = 98 to n = 65 and to n = 20, respectively. The copolymers assembled into stable vesicles at room temperature when PVPON polymerization degrees were 65 and 98. Anticancer drug DOX was entrapped with high efficiency into the aqueous PMVC58-PVPON65 polymersomal core surrounded by the hydrophobic temperature-sensitive PMVC shell and the hydrophilic PVPON corona. Unlike many liposomal, micellar, or synthetic drug delivery systems, these polymersomes exhibit an exceptionally high loading capacity of DOX (49%) and encapsulation efficiency (95%) due to spontaneous loading of the drug at room temperature from aqueous DOX solution. We also show that C57BL/6J mice injected with the lethal dose of DOX at 15 mg kg(-1) did not survive the 14 day treatment, resulting in 100% mortality. The DOX-loaded PMVC58-PVPON65 polymersomes did not cause any mortality in mice indicating that they can be used for successful DOX encapsulation. The gravimetric analyses of the animal organs from mice treated with liposome-encapsulated DOX (Lipo-DOX) and PMVC58-PVPON65 polymersomes (Poly-DOX) revealed that the Lipo-DOX injection caused some toxicity manifesting as decreased body weight compared to Poly-DOX and saline control. Masses of the left ventricle of the heart, lung, and spleen reduced in the Lipo-DOX-treated mice compared to the nontoxic saline control, while no significant decrease of those masses was observed for the Poly-DOX-treated mice. Our results provide evidence for superior stability of synthetic polymersomes in vivo and show promise for the development of next-generation drug carriers with minimal side effects.