Esophageal squamous cell carcinoma (ESCC) remains a major health challenge, with cisplatin (CDDP) being the primary chemotherapy drug, albeit accompanied by resistance development over time. This study introduces a novel platinum drug delivery system, EMLipoPt(IV), tailored to enhance platinum uptake and diminish its inactivation, providing a solution to CDDP resistance in ESCC. By synthesizing a fusion of the ESCC cell membrane with liposomal Pt(IV) prodrugs, we integrated the tumor-targeting capacity of the ESCC membrane with the inactivation resistance of Pt(IV) prodrugs. In vivo and in vitro evaluations illustrated EMLipoPt(IV)'s robustness against inactivating agents, superior tumor-targeting capacity, and remarkable ability to suppress CDDP-resistant tumor progression. Importantly, the biosafety profile of EMLipoPt(IV) surpassed existing treatments, offering a prolonged survival rate in animal models. Collectively, this work not only presents a pioneering approach in ESCC chemotherapy but also provides a blueprint for combating drug resistance in other cancers, emphasizing the broader potential for tailored drug delivery systems.