Red Blood Cell Membrane-Camouflaged Nanoparticles for Synergistic Sonodynamic Therapy and TGF-β Inhibition to Reprogram Immunosuppressive Tumor Microenvironment

Abstract Triple-negative breast cancer (TNBC) is highly metastatic and associated with a poor prognosis due to the lack of effective therapies. Current strategies focus on targeting the tumor microenvironment (TME), including immune checkpoint blockade (ICB) and transforming growth factor-β (TGF-β) pathway inhibition. Additionally, sonodynamic therapy (SDT) combined with ICB or immune modulators has demonstrated promising antitumor effects. We developed a red blood cell membrane-camouflaged nanoparticle (SB-IR-PLGA@RM) coencapsulating the sonosensitizer IR780 and the TGF-β signaling inhibitor SB431542. This biomimetic platform demonstrated enhanced tumor-targeted delivery via membrane coating technology. Under ultrasound irradiation, IR780-mediated SDT induced immunogenic cell death (ICD), promoting dendritic cell maturation and cytotoxic T lymphocyte infiltration. Concurrently, SB431542 effectively suppressed TGF-β signaling, leading to reprogramming of tumor-associated macrophages (TAMs) and neutrophils (TANs) into antitumor phenotypes, inhibition of cancer-associated fibroblasts activation (CAFs), and attenuation of epithelial-to-mesenchymal transition (EMT). This study demonstrated that SB-IR-PLGA@RM nanoparticles synergized SDT-induced ICD with TGF-β inhibition to remodel the immunosuppressive TME and amplify antitumor immunity. The integration with anti-PD-L1 (αPD-L1) provides a potent strategy against both primary and metastatic TNBC, highlighting the potential of TME-focused nanotherapeutics to overcome the limitations of conventional therapies.