Microwave‐Responsive Nanoplatform with Robust ROS Generation and Inhibiting Effects of Two‐Component System and Quorum Sensing for the Treatment of MRSA‐Induced Osteomyelitis

Abstract The hypoxic environment of deep tissue and the weak energy of microwave (MW) are still the major limitations of MW catalytic therapy. In this work, an MW‐responsive nano‐platform consisting of an Mn‐doped porphyrin metal–organic framework loaded with calcium peroxide (Mn_0.1PCC) is designed to regulate the microenvironment of the injection site and enhance the generation of reactive oxygen species. The excellent MW absorbing properties of Mn_0.1PCC improve the Fenton reaction between hydrogen peroxide formed by the hydrolysis of calcium peroxide and released Mn²⁺ generating more hydroxyl radicals under MW. This process does not consume the oxygen substrate and even produces oxygen to improve the hypoxic environment. Therefore, at a low and safe concentration (125 µg mL⁻¹), the antibacterial rate of Mn_0.1PCC against 4 × 10⁸ CFU mL⁻¹ of methicillin‐resistant Staphylococcus aureus (MRSA) after MW irradiation for 15 min is 99.71% ± 0.18%. Mn_0.1PCC, upon exposure to MW, prevents the recurrence of bacterial infections and overcomes drug resistance by inhibiting quorum sensing and the two‐component system of MRSA. It can also induce macrophage M1 polarization, up‐regulate the pro‐inflammatory factor tumor necrosis factor‐α, and enhance the phagocytosis of macrophage to bacteria. This strategy provides insights into the development of high‐performance MW‐responsive nanocomposites for the treatment of infections in deep tissues.