Abstract
The variation in tumor microenvironment, specifically the levels of cellular H2O2/O2/GSH, plays a crucial role in the effectiveness of cancer therapy in nanozyme-drug systems. In this study, bioinspired polydopamine was utilized to surface engineer the rhombic dodecahedron morphology iron-based SANzyme (Fe SANzyme), which exhibited multiple mimetic activities including oxidase (OXD)-like, peroxidase (POD)-like, catalase (CAT)-like, and glutathione peroxidase (GPx)-like activities. The Fe SAN-PDA was intricately designed as a nanoplatform for drug immobilization, remodeling the tumor microenvironment (TME) and enabling synergistic multimodal tumor therapy. The presence of abundant quinone structures on PDA surface facilitated the creation of a conductive microenvironment for the immobilization of doxorubicin (DOX) through Michael addition/Schiff base reaction. The Fe SAN-PDA@DOX can catalyze high level of H2O2 in TME to produce oxygen and alleviate hypoxia, convert the produced oxygen to the toxic ·OH, and deplete intracellular glutathione. Coating with hyaluronic acid (HA) enhanced the biocompatibility and targeting ability of the composite. The exceptional photothermal performance of Fe SAN-PDA@DOX@HA, combined with the nanozyme catalysis, resulted in sustained chemodynamic/photothermal/ chemotherapy is achieved in a mouse mammary carcinoma model. This research highlights the synergistic therapeutic effects resulting from the combination of the multi-enzymatic activities of Fe SAN with multifunctional PDA, offering a novel a novel strategy for doxorubicin immobilization, tumor microenvironment remodeling and synergistic multimodal therapy.