Ultrasound-Responsive Nanobubbles for Breast Cancer: Synergistic Sonodynamic, Chemotherapy, and Immune Activation through the cGAS-STING Pathway

Breast cancer remains the leading cause of cancer-related deaths among women worldwide, necessitating more effective treatment strategies. Chemotherapy combined with immunotherapy is the first-line treatment for breast cancer, but it still suffers from limited therapeutic efficiency and serious side effects, which are usually due to the poor delivery efficiency, drug resistance of tumor cells, and immunosuppressive tumor microenvironment. This study explores the development of ultrasound-responsive nanobubbles (Ce6/PTX Nbs) for targeted imaging and sonoimmunotherapy in breast cancer treatment. By integrating sonodynamic therapy (SDT), chemotherapy, and immunotherapy, the nanobubbles aim to address challenges such as poor drug delivery, systemic toxicity, and immune suppression in conventional therapies. The nanobubbles, composed of sonosensitizer chlorin e6 (Ce6)-modified phospholipid and loaded with the chemotherapeutic agent paclitaxel (PTX) enhancing drug-loading capacity, are designed to precisely target tumor sites via cyclic-RGD peptides. Upon ultrasound activation, Ce6 induces reactive oxygen species (ROS), promoting immunogenic cell death (ICD), while PTX disrupts tumor cell mitosis, enhancing the immune response. The nanobubbles' ultrasound responsiveness facilitates real-time imaging and controlled drug release, maximizing therapeutic efficacy while minimizing side effects. Key findings demonstrate that Ce6/PTX Nbs significantly reduced tumor growth in a 4T1 breast cancer model, enhanced immune activation via the cGAS-STING pathway, and increased the infiltration of CD8+ T cells in both primary and distant tumors. In combination with anti-PD-L1 checkpoint inhibitors, the treatment achieved a substantial suppression of tumor metastasis. This innovative approach offers a highly targeted, effective, and minimally toxic breast cancer treatment with potential for clinical translation due to its dual imaging and therapeutic capabilities.