MXene-Based Nanosheets Reverse Tumor Hypoxia to Amplify Triple-Mode Cancer Therapy

Despite MXene's good biocompatibility and photothermal properties, its poor stability in physiological environments and non-specific characteristics still pose potential risks and limit its application in the anti-tumor field. Herein, an efficient cascade catalytic system is designed by loading folic acid and bovine serum albumin-modified manganese dioxide (MnO₂) onto MXene nanosheets, improving the dispersibility of MXene in physiological environments and endowing it with active targeting capability for folate receptor-overexpressing tumors and O₂ regeneration capacity. Glucose oxidase (GOx) and L-arginine (L-Arg) are sequentially loaded onto MXene to obtain a cascade catalytic system for anti-cancer applications. MXene can be used to mediate near-infrared light-based photothermal therapy. GOx consumes intracellular glucose and generates hydrogen peroxide (H₂O₂), which can further oxidize L-Arg to generate nitric oxide and finally achieve synergy between starvation therapy and gas therapy. MnO₂ decomposes excess H₂O₂ and generates O₂, thus alleviating hypoxic inhibition of the tumor microenvironment and enhancing the effect of starvation therapy. A series of in vivo and ex vivo experiments demonstrates that the developed cascade catalytic system has much better anti-cancer effects with low toxicity and side effects, and successfully synergizes starvation/gas/photothermal therapies, which represents a novel, green, and promising strategy for cancer treatment without any chemotherapeutics.