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 MoS 2 –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 MoS 2 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 MoS 2 boosted peroxidase (POD)-like catalytic activity by facilitating Fe 3+ /Fe 2+ electron transfer for cocatalysis. In the TME, GOx depleted glucose to self-supply H 2 O 2 and gluconic acid, which activated the POD-like activity of MTFGM to decompose H 2 O 2 into toxic hydroxyl radicals ( • OH) with a maximum reaction rate 4-fold higher and turnover number 170-fold higher than pristine MoS 2 . Simultaneously, MoS 2 –TA–Fe’s glutathione peroxidase-like activity plus H 2 S n 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/H 2 S n -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.