Nontoxic bioresorbable polymersomes have been developed that efficiently and site-selectively tether targeting peptides under mild conditions with no toxic catalysts. The binding and release properties of these polymersomes have been evaluated when targeting DLD-1 human colon cancer cells overexpressing the α5β1 integrin. The delivery efficacy to these cells is markedly improved over commonly used RGD targeting peptides by use of an α5β1-specific targeting peptide, PR-b. Release profiles in buffered solution from pH 7.4 to 4.5 were evaluated and compared to release after binding to cells, and enzymatic degradation was identified as a major cause of rapid payload release in the cell. Intracellular trafficking and release were imaged via confocal microscopy in live cells and colocalization with organelles was evaluated quantitatively over time. Finally, the anticancer drug cisplatin was encapsulated in the PR-b functionalized polymersomes and the presence of PR-b greatly improved delivery efficacy, with increased cisplatin-induced losses to targeted DLD-1 colon cancer cell viability. When delivered to CACO-2 model human epithelial cells expressing low levels of α5β1 integrin, low toxicity was maintained, suggesting that targeting was specific to α5β 1 overexpressing cells. These results demonstrate that PR-b-functionalized bioresorbable polymersomes may be an attractive route to minimizing the dose-limiting side effects associated with existing approaches to cisplatin chemotherapy.