Low-intensity pulsed ultrasound (LIPUS)-augmented calcicoptosis by calcium-based nanoparticles for enhanced immunogenic cell death induction in triple-negative breast cancer

Triple-negative breast cancer (TNBC) shows limited therapeutic efficacy due to the absence of effective targeted treatment options, with its immunosuppressive tumor microenvironment further diminishing the effectiveness of immunotherapy. Intracellular Ca²⁺ homeostasis plays a critical role in cancer progression, yet the efficacy of traditional inorganic nanoparticles in inducing calcicoptosis through Ca²⁺ release is constrained by poor water solubility, stability, and delivery efficiency. To address these challenges, we developed novel nanoparticles (NPs) by coordinating Ca²⁺ with the natural bioactive compound glycyrrhizic acid to create a multifunctional carrier (GC NPs), which was further loaded with the therapeutic natural compound curcumin (CUR) to form GC@CUR NPs. Through synergistic effects of Ca²⁺ overload and CUR-mediated regulation, these NPs significantly promote Ca²⁺ accumulation in mitochondria, triggering mitochondrial dysfunction and efficiently inducing calcicoptosis. Additionally, low-intensity pulsed ultrasound (LIPUS)-mediated targeted release markedly improved antitumor effects. Importantly, this strategy effectively induces immunogenic cell death (ICD) in TNBC, thereby significantly boosting antitumor immune responses. This study provides an innovative and efficient strategy for integrating chemotherapy and immunotherapy to transform TNBC tumors into immunoresponsive ones, offering new possibilities for comprehensive TNBC treatment.