LAUSR

The high heterogeneity of basal‐like breast cancer (BLBC) and the absence of effective therapeutic targets pose ongoing treatment challenges. Pyroptosis, a type of cell death characterized by cell swelling and membrane perforation, offers a promising therapeutic weathervane for BLBC, particularly when induced by physical therapies. In this study, a high‐intensity focused ultrasound (HIFU)‐driven targeted pyroptosis strategy is developed for BLBC therapy. Through integration of HIFU‐driven gene regulation analysis and bioinformatics analysis of pyroptosis‐related genes from the TCGA dataset, 20 potential pyroptosis inducers are identified to work synergistically with HIFU. Mitoxantrone, a promising inducer, is encapsulated in platelet membrane‐hybridized liposomes to enhance targeted delivery and therapeutic efficacy. Importantly, the combination of HIFU and Plp enhanced tumor delivery of liposomes by 2.46 fold and dramatically inhibited tumor growth, with 50% of female BALB/c mice remaining tumor‐free compared to liposome‐only treatment. Mechanistically, HIFU significantly downregulated the expression of histone deacetylases 4 and 9, while promoting cathepsin‐L (CTSL) gene transcription. Simultaneously, Plp and HIFU synergistically suppressed BCL‐2 via CTSL, increasing ROS production. This activated Caspase8 and the NLRP3 inflammasome, leading to GSDMC cleavage and initiating pyroptosis. Collectively, this study provides an innovative pyroptosis therapy strategy combining physical treatment and chemotherapy for BLBC and other refractory diseases.