A Vacancy‐Engineering Ferroelectric Nanomedicine for Cuproptosis/Apoptosis Co‐Activated Immunotherapy

Low efficacy of immunotherapy due to the poor immunogenicity of most tumors and their insufficient infiltration by immune cells highlights the importance of inducing immunogenic cell death and activating immune system for achieving better treatment outcomes. Herein, ferroelectric Bi2CuO4 nanoparticles with rich copper vacancies (named BCO‐VCu) are rationally designed and engineered for ferroelectricity‐enhanced apoptosis, cuproptosis, and the subsequently evoked immunotherapy. In this structure, the suppressed recombination of the electron–hole pairs by the vacancies and the band bending by the ferroelectric polarization lead to high catalytic activity, triggering reactive oxygen species bursts and inducing apoptosis. The cell fragments produced by apoptosis serve as antigens to activate T cells. Moreover, due to the generated charge by the ferroelectric catalysis, this nanomedicine can act as “a smart switch” to open the cell membrane, promote nanomaterial endocytosis, and shut down the Cu+ outflow pathway to evoke cuproptosis, and thus a strong immune response is triggered by the reduced content of adenosine triphosphate. Ribonucleic acid transcription tests reveal the pathways related to immune response activation. Thus, this study firstly demonstrates a feasible strategy for enhancing the efficacy of immunotherapy using single ferroelectric semiconductor‐induced apoptosis and cuproptosis. BCO‐VCu induces apoptosis by triggering a burst of reactive oxygen species under ultrasound irradiation; it acts as a switch to reduce Cu+ efflux and alterations in proteins such as dihydrolipoic acid S‐acetyltransferase, ferredoxin 1, inducing the occurrence of cuproptosis. More importantly, it triggers immunogenic cell death, which causes a strong immune response.