Synergistic ROS/RNS-Mediated Chemotherapy via M1 Macrophage Membrane-Functionalized Nanovesicles for Targeted Hepatocellular Carcinoma Treatment

Reactive species chemistry, encompassing both broad-spectrum reactive oxygen species (ROS) and reactive nitrogen species (RNS), has received significant attention in cancer therapeutics due to its capacity to induce severe oxidative damage and subsequent cancer cell death. Here in this study, we developed M1 macrophage membrane-coated MnO₂-silica containing doxorubicin (DOX) and NO donor (M1@MS/MnO₂/DOX/NO) for the combination of reactive species, including both ROS and RNS for hepatocellular carcinoma therapy. Specifically, superoxide anion O₂ ^•- produced from DOX could react with NO to form ONOO- for RNS-mediated treatment. Meanwhile, Mn²⁺ produced from the MnO₂ layer under a reductive microenvironment could function as a catalyst to transform endogenous H₂O₂ into the highly toxic ^•OH to achieve ROS-mediated treatment. Our results demonstrated that this novel combination of reactive species therapy synergistically improved the therapeutic efficiency against liver cancer cells, and showed a significant reduction of cancer cell proliferation and in vivo tumor growth.