Fe/N-doped hollow carbon nanozymes for synergistic chemo-photothermal-catalytic therapy via tumor microenvironment remodeling

The limited penetration and efficacy of chemotherapeutic agents, constrained by the distinctive pathophysiological conditions of the tumor microenvironment (TME), remain a major therapeutic obstacle. In recent years, there has been growing interest in modulating the TME to overcome these barriers, which provides a promising way for enhancing cancer treatment. To address this challenge, a multifunctional nanoparticle system (DOX/FeNHC-PEG) was developed for oxidative stress-augmented triple-modal therapy. The system was constructed by doping Fe 3+ ions and N atoms into hollow carbon nanostructures, followed by surface functionalization with NH₂-PEG and subsequent loading of doxorubicin (DOX) into its mesoporous cavities. FeNHC-PEG nanozyme exhibited remarkable multi-enzyme mimetic activities, consuming endogenous glutathione while generating substantial OH through the peroxidase (POD)-like and oxidase (OXD)-like activities, thereby intensifying tumor oxidative stress. Furthermore, the nanozyme demonstrated excellent photothermal conversion efficiency under NIR irradiation. Crucially, real-time shear wave elastography (SWE) revealed that the combined effects of photothermal therapy (PTT) and reactive oxygen species (ROS) significantly reduced tumor viscoelasticity by degrading extracellular matrix components. The change not only enhanced intertumoral drug penetration but also cooperated with persistent oxidative stress to remodel the tumor microenvironment, ultimately leading to a significant increase in chemosensitivity to DOX. Meanwhile, the localized hyperthermia further potentiated the enzyme-like activities, enabling amplified ROS generation. In vivo studies indicated that DOX/FeNHC-PEG exhibited outstanding biocompatibility and potent tumor growth suppression (95.8% ± 1.8% inhibition) with negligible systemic toxicity. The triple-synergistic therapy system represented an innovative approach for tumor microenvironment remodeling, showing considerable translational potential.