Orchestrating enhanced starvation and ROS storm therapy with MnO2 nanozyme-driven cascade nanoreactors

The therapeutic efficacy of glucose oxidase (GOx)-mediated starvation therapy and β-Lapachone (LPC)-induced oxidative stress is significantly constrained by tumor hypoxia and elevated antioxidant defenses in the tumor microenvironment. To address these limitations, a multifunctional nanoplatform, LPC/GOx@ZIF-8@MnO 2 , was developed through the integration of LPC and GOx within a zeolitic imidazolate framework-8 (ZIF-8) carrier followed by surface modification with manganese dioxide (MnO 2 ), and its antitumor efficacy and mechanistic basis were systematically evaluated using HeLa cells in vitro and U14 tumor-bearing mouse models in vivo . Comprehensive in vitro and in vivo studies demonstrated significant tumor growth inhibition with excellent biosafety, while mechanistic investigations revealed that this nanocomposite achieves synergistic antitumor effects through four coordinated mechanisms: MnO 2 -catalyzed conversion of endogenous hydrogen peroxide to oxygen alleviates hypoxia while sustaining GOx-mediated glucose depletion; a self-amplifying cascade reaction enhances LPC-induced reactive oxygen species (ROS) generation; photothermally activated upregulation of NAD(P)H:quinone oxidoreductase 1 (NQO1) via the heat shock protein 70 (HSP70)/NQO1 axis enhances LPC efficacy; and depletion of glutathione disrupts cellular antioxidant defenses. Furthermore, it was also revealed that LPC/GOx@ZIF-8@MnO 2 acts on caspase-3, high mobility group box 1 (HMGB1), and matrix metalloproteinase-1 (MMP-1) to coordinate apoptosis induction and metastasis suppression, with molecular docking further clarifying the key binding sites of LPC with these three targets. Collectively, this work presents an innovative strategy to overcome therapeutic limitations imposed by tumor hypoxia, provides molecular-level insights into multimodal synergistic therapy, and offers new ideas for precision tumor therapy.