Self-Assembled Spatially Confined Mo-Based Nanoreactor for Multimechanistic Tumor Therapy Driven by Self-Cascade Catalysis

Addressing the stability-activity imbalance of natural enzyme-nanozyme self-cascade catalysis for tumor-specific therapy while inhibiting tumor metastasis via multiple killing mechanisms remains a challenge. Herein, we constructed a tumor microenvironment (TME)-responsive mannose-modified MoS2-tannic acid (TA)-Fe-glucose oxidase (GOx) nanoreactor (MTFGM) via a spatial confinement strategy relying on metal-polyphenol coordination and electrostatic interactions for addressing this issue. GOx was confined on MoS2 via hydrogen bonds and π-π stacking. TA's polyphenol network and mannose's shielding effect enhanced GOx stability by preventing off-target catalysis, while TA-Fe on MoS2 boosted peroxidase (POD)-like catalytic activity by facilitating Fe3+/Fe2+ electron transfer for cocatalysis. In the TME, GOx depleted glucose to self-supply H2O2 and gluconic acid, which activated the POD-like activity of MTFGM to decompose H2O2 into toxic hydroxyl radicals (•OH) with a maximum reaction rate 4-fold higher and turnover number 170-fold higher than pristine MoS2. Simultaneously, MoS2-TA-Fe's glutathione peroxidase-like activity plus H2Sn production continuously consumed glutathione (GSH) to break tumor antioxidant defense. This cascade synergistically induced four tumor-killing mechanisms: GOx-mediated metabolic starvation, •OH-triggered apoptosis, GSH depletion-driven ferroptosis, and cystine accumulation/H2Sn-induced disulfidptosis collectively disrupt tumor redox homeostasis and inhibit metastasis. Our work clarifies the structure-activity relationship of confinement-based cascade nanoreactors and provides a TME-responsive multiple cell death paradigm for tumor-specific therapy.