<p>The abnormally high expression of glutathione (GSH) in hepatocellular carcinoma (HCC) cells significantly contributes to chemotherapy resistance by neutralizing reactive oxygen species (ROS). To address this problem, we developed a nanocomposite probe (micelle@PDA@MnO₂ NPs) which was composed of free radical-labeled micelles as the core, polydopamine (PDA) as the inner shell and MnO₂ nanosheets as the outer shell. In the HCC microenvironment, the over-expressed GSH triggered the decomposition of the MnO₂ shell, releasing Mn²⁺ ions, and subsequently, the acidic condition and over-expressed carboxylesterase 2 (CES2) worked together to mediate the controlled release of nitroxide free radicals (i.e., TEMPONE) from the micelle core. With the help of dual-signal electron spin resonance (ESR) detection, it was found that much more free radicals and Mn²⁺ were released in hepatoma cells than in normal liver cells, rendering the proposed nanotherapeutic platform specific to HCC and a good candidate for free radical therapy and chemodynamic therapy (CDT). Moreover, the therapy featured an intelligent self-amplified property: the abundant GSH in the tumor microenvironment rapidly activated the decomposition of the nanocomposite and triggered the release of free radical TEMPONE and Mn²⁺, and TEMPONE and Mn²⁺ further amplified the oxidative stress to induce tumor apoptosis via ROS generation and GSH depletion. Finally, in combination with three therapy modes (Mn²⁺-mediated CDT, the oxidative stress enhancement effect of TEMPONE, and PDA-based photothermal therapy), significant therapeutic effects including facilitation of HepG2 cell apoptosis and inhibition of tumor growth in the HCC mouse model were achieved.</p>