Ultrasound nanodroplets loaded with Siglec-G siRNA and Fe3O4 activate macrophages and enhance phagocytosis for immunotherapy of triple-negative breast cancer

The progression of triple-negative breast cancer is shaped by both tumor cells and the surrounding tumor microenvironment (TME). Within the TME, tumor-associated macrophages (TAMs) represent a significant cell population and have emerged as a primary target for cancer therapy. As antigen-presenting cells within the innate immune system, macrophages are pivotal in tumor immunotherapy through their phagocytic functions. Due to the highly dynamic and heterogeneous nature of TAMs, re-polarizing them to the anti-tumor M1 phenotype can amplify anti-tumor effects and help mitigate the immunosuppressive TME. In this study, we designed and constructed an ultrasound-responsive targeted nanodrug delivery system to deliver Siglec-G siRNA and Fe3O4, with perfluorohexane (PFH) at the core and mannose modified on the surface (referred to as MPFS@NDs). Siglec-G siRNA blocks the CD24/Siglec-G mediated "don't eat me" phagocytosis inhibition pathway, activating macrophages, enhancing their phagocytic function, and improving antigen presentation, subsequently triggering anti-tumor immune responses. Fe3O4 repolarizes M2-TAMs to the anti-tumor M1 phenotype. Together, these components synergistically alleviate the immunosuppressive TME, and promote T cell activation, proliferation, and recruitment to tumor tissues, effectively inhibiting the growth of primary tumors and lung metastasis. This work suggests that activating macrophages and enhancing phagocytosis to remodel the TME could be an effective strategy for macrophage-based triple-negative breast cancer immunotherapy.