Intelligent manganese dioxide nanocomposites induce tumor immunogenic cell death and remould tumor microenvironment

The solid tumor often has unique structure and microenvironment that quite different with normal tissue. The tumor microenvironment (TME) of solid tumor is often characterized by mild acid, high glutathione (GSH) level, excessive hydrogen peroxide (H2O2) and hypoxia. These characteristics not only accelerate tumor progression, angiogenesis and metastasis, but also lead to drug resistance and treatment failure. To regulate these adverse factors in TME plays vital roles in improving tumor response to various treatments. In this study, a silk fibroin-cRGDfk-Ce6 conjugate-based MnO2 nanocomposite (SRCM) was fabricated, and its modulation potentials of these adverse factors, enhanced immune cell activation and infiltration in TME were systematically studied in vitro and in vivo. After administration in vivo, the synthesized SRCM quickly targeted to acidic TME, reduced to ultra-small nanosheets and Mn2+, triggered the endogenous H2O2 decomposition and oxygen generation, and converted GSH into GSSG. Therefore, to modulate the adverse factors in TME, while Mn2+ simultaneously enhanced the magnetic resonance imaging (MRI) capability. Together with photodynamic therapy (PDT) and photothermal therapy (PTT), the SRCM effectively induced immunogenic cell death (ICD), antigen-presenting cell (APC) activation, and improved immune-competent cell infiltration. The results demonstrated that the SRCM not only alleviated hypoxia in TME, enhanced PDT efficacy, but also efficiently induced the IDC of tumor cells, corrected the adverse physical, chemical and biological factors in TME, thereby effectively reducing the tumor burden in animal model.