Mn-CaCO3-based nanosystem for augmented sonodynamic-chemodynamic immunotherapy via PI3K/Akt signaling pathway

Cancer immunotherapy has improved the survival rate of patients with malignant tumors. However, the response of solid tumors to immunotherapy is quite limited. Here, we report a pH-responsive nanocomposite for augmented sonodynamic-chemodynamic immunotherapy. This Mn-CaCO3-2,2′-azobis[2-(2-imidazolin-2-yl) propane]-dihydrochloride (AIPH) nanosystem, Lipo@MCA, was prepared through a simple two-step reaction. It released sonosensitizer AIPH and Ca2+ within the acidic tumor microenvironment. AIPH generated alkyl free radicals under ultrasound irradiation, and Mn2+ produces ·OH through Fenton-like reaction. The Ca2+ induced calcium overload in tumor cells. This induced mitochondrial dysfunction and promoted tumor cell apoptosis. Lipo@MCA also inhibited the phosphorylation of Akt and PI3K. In vitro experiments indicated that the nanoparticle inhibited tumor cell invasion and migration, and induced tumor cell apoptosis. In vivo experiments demonstrated that Lipo@MCA inhibited tumor growth by promoting cytokine secretion, stimulating dendritic cell maturation, and enhancing T-cell differentiation. In summary, this study paves the way for synergistic inhibition of tumor cell metastasis and immunotherapy in solid tumors through PI3K signaling pathway inhibition.