To meet the requirements on both delivery stability during blood circulation and fast intracellular release for water-soluble chemotherapeutics encapsulated in polymersomes. A shell photo-crosslinked and esterase-sensitive polymersome (C-PEAMP-D) was constructed based on amphiphilic polyphosphazene PEAMP containing 2-aminoethyl methacrylate. The leakage of doxorubicin hydrochloride (DOX·HCl) was significantly inhibited from 42.27 to 26.64% in 10h and the accelerated intracellular DOX·HCl release occurred responsively to the esterase at high concentration in cancer cells. Consequently, C-PEAMP-D achieved better antitumor efficiency when compared with free DOX·HCl and uncrosslinked PEAMP vesicle. We provided a strategy to conquer drug leakage in systemic circulation and trigger enzyme-sensitive drug release inside cancer cells for improving oncotherapy outcome of water-soluble chemotherapeutics.