Dual-Drug nanoparticles activate pyroptosis in cancer cells synergistically target cancer stem cells to augment chemoimmunotherapy of triple-negative breast cancer

The limited immunogenic cell death (ICD) in tumors, particularly the difficulty in inducing pyroptosis, along with the persistence of breast cancer stem cells (BCSCs), lead to treatment resistance, relapse and metastasis in triple-negative breast cancer (TNBC). To counter these issues, a dual-drug nanoparticle was created by optimizing the encapsulation of clinical decitabine (DCT) and doxorubicin (DOX) into poly(lactic-co-glycolic acid) with a hyaluronic acid modification (DD@PH NPs). This platform targeted both TNBC cells and BCSCs via hyaluronic acid mediation. In 4 T1 cells, DCT was firstly and rapidly released from DD@PH NPs with programmed release feature to induce the up-regulation of gasdermin E through DNA demethylation, and then DOX was significantly released in acidic tumor environments to activate caspase-3 via mitochondrial damage. This process synergistically instigates pyroptosis in otherwise pyroptosis-resistant breast cancer cells, thereby enhancing ICD. Furthermore, the dual-drug release could depolymerize and eliminate BCSCs. Critically, this tumor pyroptosis and BCSCs death triggered a potent anti-tumor immune response, in terms of activating dendritic cells and T cells, and polarizing M2-type macrophages into M1-type. This immune response further inhibited both 4 T1 cells and BCSCs. As a result, the synergistic chemoimmunotherapy of DD@PH NPs led to improved therapeutic outcomes. These include significant inhibition of tumor development and metastasis in TNBC, demonstrating the potential from this nanomedicine for efficient TNBC treatment.