Supramolecular delivery systems with prolonged circulation, potential for diverse functionalization, and few toxin-related limitations have been extensively studied. For the present study, we constructed the linear polyglycerol-shelled polymersome attached with the anti-HER-2-antibody trastuzumab. We then covalently loaded the anti-cancer drug DM1 in the polymersome via dynamic disulfide bonding. The resulted Trastuzumab-polymersome-DM1 (Tra-PS-DM1) exhibits a mean size of 95.3 nm and a remarkable drug loading efficiency% of 99.3%. In addition to its superior stability, we observed rapid release of DM1 in a controlled manner under reductive conditions. Compared to the native polymersomes, Tra-PS-DM1 has shown greatly improved cellular uptake and significantly reduced IC50 up to 17-fold among HER-2 positive cancer cells. Moreover, Tra-PS-DM1 demonstrated superb growth inhibition of HER-2 positive tumoroids, specifically BT474 tumoroids shrunk up to 62% after 12 h treatment. With exceptional stability and targetability, PG-shelled Tra-PS-DM1 appears to emerge as an attractive approach for HER-2-positive tumor treatment.