Gestational choriocarcinoma (CC) is a rare and highly malignant cancer originating from the trophoblastic layers of the placenta. Currently, methotrexate (MTX) is the first-line treatment for CC; however, due to the aggressive and metastatic nature of CC, multiple doses are often required, leading to severe side effects from the lack of tumor specificity. The first targeted MTX-loaded polymersomes (Ps) designed for efficient drug delivery to CC tumors are introduced. The modification of these Ps nanoplatforms with guanosine (Gn), which targets the ENT-1 transporter overexpressed in CC cells, significantly enhances tumor uptake. Upon internalization by CC cells, the disulfide bonds in the Ps are reduced by high intracellular glutathione levels, causing Ps disintegration and efficient drug release. Biodistribution studies also reveal significant accumulation in subcutaneous CC tumors with minimal distribution in major organs. The ENT-1-targetedpolymersomes show twice the tumor accumulation compared to the nontargeted ones based on in-vivo fluorescence imaging. ENT-1-targeted MTX-loaded polymersomes (Gn-MTX@SS-Ps) achieve significantly greater tumor shrinkage in mice, reducing tumors by 30% more than nontargeted MTX@SS-Ps and 75% more than free MTX at the same dosage regimen. Consequently, developed CC-targeted MTX-loaded polymer-based delivery system holds the potential to significantly enhance the treatment of CC.