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.BACKGROUNDThe 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.RESULTSIn 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. Fe3