Mesoporous SiO2 based nanocomplex enzymes for enhanced chemodynamic therapy of pancreatic tumors

Abstract

Chemodynamic therapy (CDT) is a therapeutic method that uses a Fenton/Fenton-like reaction to convert intracellular H₂O₂ into highly cytotoxic ˙OH to effectively kill cancer cells. This method is adapted to the specific characteristics of the tumor microenvironment, boasting high selectivity and strong specificity among other advantages. However, CDT still faces challenges. Glutathione (GSH), which is present in high levels in the tumor microenvironment, can consume a large amount of ˙OH, significantly limiting the effectiveness of CDT. In this study, we synthesized a core–shell nanozyme (mSiO₂@MnO₂) with a composite structure comprising a mesoporous silica core and a manganese dioxide (MnO₂) shell. The mesoporous structure was loaded with the chemotherapeutic drug genistein (Gen) and surface-modified with polyethylene glycol (PEG) to enhance its effectiveness in treating pancreatic cancer. This formulation, denoted as the Gen@mSiO₂@MnO₂-PEG nanocomplex enzyme, exhibits a dual action mechanism. Firstly, upon reaching tumor cells, it releases genistein for kinetic therapy and degrades the MnO₂ shell. Secondly, GSH consumption triggers Fenton-like reactions to generate ˙OH, thereby enhancing CDT. At the cellular level, the Gen@mSiO₂@MnO₂-PEG nanocomplex enzyme demonstrates excellent biocompatibility. It induces the production of reactive oxygen species in the pancreatic cancer cell line PANC-1, disrupting the redox balance within tumor cells, and ultimately killing them. In vivo, the Gen@mSiO₂@MnO₂-PEG nanocomplex enzyme selectively accumulates at the tumor sites in PANC-1 tumor-bearing mice, resulting in the inhibition of tumor growth and metastasis. This study demonstrates that core–shell nanozymes serve as an effective platform for cancer therapy, enhancing the efficacy of combined chemotherapy and CDT for pancreatic cancer.