Sm/Co‐Doped Silica‐Based Nanozymes Reprogram Tumor Microenvironment for ATP‐Inhibited Tumor Therapy

Abstract Current applications of multifunctional nanozymes for reprogramming the redox homeostasis of the tumor microenvironment (TME) have been severely confronted with low catalytic activity and the ambiguity of active sites of nanozymes, as well as the stress resistance from the rigorous physical environment of tumor cells. Herein, the Sm/Co‐doped mesoporous silica with 3PO‐loaded nanozymes (denoted as mSC‐3PO) are rationally constructed for simultaneously inhibiting energy production by adenosine triphosphate (ATP) inhibitor 3PO and reprogramming TME by multiactivities of nanozymes with photothermal effect assist, i.e., enhanced peroxidase‐like, catalase‐like activity, and glutathione peroxidase‐like activities, facilitating reactive oxygen species (ROS) generation, promoting oxygen content, and restraining the over‐expressed glutathione. Through the optimal regulation of nanometric size and doping ratio, the fabricated superparamagnetic mSC‐3PO enables the excellent exposure of active sites and avoids agglomeration owing to the large specific surface and mesoporous structure, thus providing adequate Sm/Co‐doped active sites and enough spatial distribution. The constructed Sm/Co centers both participate in the simulated biological enzyme reactions and carry out the double‐center catalytic process (Sm 3+ and Co 3+ /Co 2+ ). Significantly, as the inhibitor of glycolysis, 3PO can reduce the ATP flow by cutting down the energy transform, thereby inhibiting tumor angiogenesis and assisting ROS to promote the early withering of tumor cells. In addition, the considerable near‐infrared (NIR) light absorption of mSC‐3PO can adapt to NIR excitable photothermal treatment therapy and photoexcitation‐promoted enzymatic reactions. Taken together, this work presents a typical therapeutic paradigm of multifunctional nanozymes that simultaneously reprograms TME and promotes tumor cell apoptosis with photothermal assistance.