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Sonodynamic therapy (SDT) has emerged as a promising modality for treating deep-seated tumors. It has been demonstrated that SDT effectively induces immunogenic cell death (ICD), thereby initiating a systemic anti-tumor immune response - a process known as sonodynamic immunotherapy. However, its efficacy is severely limited by the hypoxic tumor microenvironment (TME) and elevated glutathione (GSH) levels, which together scavenge reactive oxygen species (ROS) and create a potent antioxidant barrier.

Ultra-small Mn₃O₄ nanoparticles with multi-enzyme mimicking activity were synthesized, and co-encapsulated with the sound sensitizer Ag₂S quantum dot (Ag₂S QD) in cell membrane hybrid liposomes to construct a biomimetic nanoplatform (Mn₃O₄/QD@LM). The Catalase and glutathione peroxidase activities of Mn₃O₄/QD@LM were evaluated. Its antitumor efficacy in vitro was evaluated by measuring ROS levels, mitochondrial membrane potential staining, live/dead cell staining, and apoptosis analysis. By recording tumor growth and performing histological and immunohistochemical examinations, its antitumor effects in vivo were investigated in a mouse model of colon cancer. Flow cytometry analysis was used to analyze the tumor immune microenvironment.

Mn₃O₄/QD@LM functioned as a "ROS amplifier" by exhibiting catalase-like and glutathione peroxidase-like activities, which alleviated tumor hypoxia and depleted GSH, thereby markedly enhancing SDT efficacy. Moreover, released Mn²⁺ ions generated highly cytotoxic hydroxyl radicals via a Fenton-like reaction, further augmenting tumor cell killing. In vitro experiments confirmed that Mn₃O₄/QD@LM effectively induced ICD and activated the STING pathway. Benefiting from homologous targeting, the nanoplatform achieved efficient accumulation in tumor tissue in vivo. Upon ultrasound activation, Mn₃O₄/QD@LM significantly inhibited tumor growth both in vitro and in vivo. Notably, it remodeled the tumor immune microenvironment by promoting CD8⁺ T cell infiltration, enhancing the secretion of IFN-γ and TNF-α, and reducing the populations of regulatory T cells and myeloid-derived suppressor cells.

Mn₃O₄/QD@LM confirms the synergistic role of multi-enzyme activities and STING pathway activation in potentiating sonodynamic immunotherapy, and provides an innovative strategy to overcome TME-mediated therapy resistance.