Tumor Microenvironment-Activated\nIn Situ Synthesis\nof Peroxynitrite for Enhanced Chemodynamic Therapy

Chemodynamic therapy (CDT) can induce cancer cell death\nthrough\nhydroxyl radicals (·OH) generated from Fenton or Fenton-like\nreactions. Compared with traditional therapies, CDT effectively overcomes\ninevitable drug resistance and exhibits low side effects. However,\nclinical application still faces challenges, primarily due to insufficient\n·OH generation and the short-lifetime of ·OH in vivo. To\naddress these challenges, we developed a peroxynitrite (ONOO<sup>–</sup>)-based CDT nanodrug (DOX@PMOF) composed of MOF-199, NO donor (PArg),\nand nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator\n(doxorubicin, DOX). In DOX@PMOF, MOF-199 serves as both a carrier\nfor loading DOX and a source of Cu<sup>+</sup> for triggering CDT.\nUpon uptake by cancer cells, the high concentration of glutathione\n(GSH) reduces MOF-199 to Cu<sup>+</sup>, which then reacts with H<sub>2</sub>O<sub>2</sub> to generate ·OH. Moreover, the released\nDOX upregulates NOX4 expression, leading to the elevated H<sub>2</sub>O<sub>2</sub> level and thereby promoting a high-efficiency Fenton-like\nreaction for sufficient ·OH generation. Subsequently, PArg generates\nabundant NO in response to the tumor microenvironment, leading to\na cascade of NO and ·OH for the in situ synthesis of ONOO<sup>–</sup>. ONOO<sup>–</sup> is more toxic and has a longer\nlifetime and diffusion distance than ·OH, resulting in a more\neffective CDT treatment. To further enhance the in vivo therapeutic\neffect, we coated DOX@PMOF with a homologous cell membrane to form\nan active tumor-targeting nanodrug (DOX@MPMOF), which has demonstrated\nthe ability to effectively inhibit tumor growth and metastasis while\nexhibiting good biosafety.