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Cytotoxicity can in principle be maximized if drugs with different activities can be delivered simultaneously to the same cell. However, combination therapy with drugs having distinct properties such as solubility generally requires use of multiple carriers or solvents, limiting the likelihood of simultaneous delivery. In this brief report, we describe the in vivo use of biodegradable polymersomes for systemic delivery of an anticancer cocktail. These polymer-based shells exploit a thick hydrophobic membrane and an aqueous lumen to efficiently carry both hydrophobic and hydrophilic drugs, respectively paclitaxel and doxorubicin. Polymersomes are long-circulating in vivo but also degrade and release their drugs on a time scale of about 1 day, by which time the tumors treated here will otherwise have almost doubled in volume. A single systemic injection of the dual drug combination shows a higher maximum tolerated dose than the free drug cocktail and shrinks tumors more effectively and more sustainably than free drug: 50% smaller tumors are seen at 5 days with polymersomes. The polymersomes cause two-fold higher cell death in tumors than free drug and show quantitatively similar increases in maximum tolerated dose and drug accumulation within the tumors—suggesting promise for multi-drug delivery.