Triggering Pyroptosis\nby Doxorubicin-Loaded Multifunctional\nNanoparticles in Combination with Decitabine for Breast Cancer Chemoimmunotherapy

Pyroptosis, a form of programmed cell death, holds great\npromise\nfor breast cancer treatment. However, the downregulation of gasdermin\nE (GSDME) limits the effectiveness of pyroptosis. To address this\nchallenge, we developed a folic acid-modified and glutathione/reactive\noxygen species dual-responsive nanocarrier (FPSD NPs) for the targeted\ndelivery of doxorubicin (DOX). Through the combination with DNA methyltransferase\ninhibitor decitabine (DAC), the GSDME protein expression was significantly\nincreased in 4T1 cells, resulting in cell swelling and ballooning,\nwhich are characteristic features of pyroptosis. In vivo experiments\nfurther demonstrated the antitumor efficacy of DAC + DOX@FPSD NPs,\nand the 4T1-bearing mice treated with DAC + DOX@FPSD NPs exhibited\nreduced tumor volumes, minimized tumor weights, decreased Ki67-positive\ncells, increased TUNEL apoptosis ratios, and pronounced lesions in\nH&E staining. Furthermore, DAC + DOX@FPSD NP treatment could promote\npyroptosis-associated antitumor immunity, as evidenced by the increased\npresence of CD3<sup>+</sup>, CD4<sup>+</sup>, and CD8<sup>+</sup> T\ncells, heightened secretion of tumor necrosis factor-α and interferon-γ,\nelevated high-mobility group box-1 levels, and enhanced calreticulin\nexposure. The FPSD nanocarrier developed in this study had favorable\nstability, active targeting ability, biocompatibility, and controlled\nrelease properties, and the DAC + DOX@FPSD NPs represented an approach\nto antitumor therapy by inducing pyroptosis, which offers a promising\navenue for breast cancer treatment.