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.