Triggering Pyroptosis by Doxorubicin-Loaded Multifunctional Nanoparticles in Combination with Decitabine for Breast Cancer Chemoimmunotherapy.

Pyroptosis, a form of programmed cell death, holds great promise for breast cancer treatment. However, the downregulation of gasdermin E (GSDME) limits the effectiveness of pyroptosis. To address this challenge, we developed a folic acid-modified and glutathione/reactive oxygen species dual-responsive nanocarrier (FPSD NPs) for the targeted delivery of doxorubicin (DOX). Through the combination with DNA methyltransferase inhibitor decitabine (DAC), the GSDME protein expression was significantly increased in 4T1 cells, resulting in cell swelling and ballooning, which are characteristic features of pyroptosis. In vivo experiments further demonstrated the antitumor efficacy of DAC + DOX@FPSD NPs, and the 4T1-bearing mice treated with DAC + DOX@FPSD NPs exhibited reduced tumor volumes, minimized tumor weights, decreased Ki67-positive cells, increased TUNEL apoptosis ratios, and pronounced lesions in H&E staining. Furthermore, DAC + DOX@FPSD NP treatment could promote pyroptosis-associated antitumor immunity, as evidenced by the increased presence of CD3 ⁺ , CD4 ⁺ , and CD8 ⁺ T cells, heightened secretion of tumor necrosis factor-α and interferon-γ, elevated high-mobility group box-1 levels, and enhanced calreticulin exposure. The FPSD nanocarrier developed in this study had favorable stability, active targeting ability, biocompatibility, and controlled release properties, and the DAC + DOX@FPSD NPs represented an approach to antitumor therapy by inducing pyroptosis, which offers a promising avenue for breast cancer treatment.