Liquid metal-based nanocomposite with triple-amplified Fenton-like reaction for tumor chemodynamic/photothermal/immunotherapy

Chemodynamic therapy (CDT) combined with immunotherapy has emerged as a promising strategy for tumor treatment. However, the inefficiency of CDT and immunosuppressive tumor microenvironment (ITM) limit the overall effectiveness of this approach. In this study, a manganese-doped mesoporous silica-coated liquid metal nanocomposite, coloaded with small-sized aurum (Au) nanoparticles (NPs) and 1-methyltryptophan (1MT) (denoted as LMSMA1), was developed to improve the efficiency of CDT and reverse ITM. First, the LMSMA1 NPs could consume intracellular overexpressed glutathione (GSH), facilitating Fenton-like ion transfer while reducing GSH-mediated clearance of reactive oxygen species (ROS), thereby enhancing CDT. Second, the intracellular glucose was oxidized to hydrogen peroxide (H₂O₂) by glucose oxidase (GOx)-mimicking Au NPs, providing an H₂O₂ boost that further amplified CDT. Additionally, the LMSMA1 NPs increased the local tumor temperature upon near-infrared (NIR) laser irradiation, achieving photothermal therapy (PTT)-enhanced CDT. The resulting triple-amplified Fenton-like reaction induced significant intracellular oxidative stress to cause tumor cell death. For immunotherapy, the activation of cGAS-STING pathway and immunogenic cell death (ICD) resulting from manganese ions (Mn²⁺) and PTT/CDT could elicit an immune response and subsequently activate cytotoxic T cells. Simultaneously, the released 1MT inhibited indoleamine 2,3-dioxygenase (IDO), suppressing the function of regulatory T cells. This, in turn, alleviated the immunosuppressive microenvironment and reinforced the anti-tumor immune response. In summary, this strategy established a highly feasible concept for integrating triple-amplified CDT with immunotherapy.