Acid‐Responsive H2‐Releasing 2D MgB2Nanosheet for Therapeutic Synergy and Side Effect Attenuation of Gastric Cancer Chemotherapy

The hydrogen molecule is recognized as a high potential to attenuate toxic side effects of chemotherapy and also enhance chemotherapeutic efficacy, and the development of a novel hydrogen‐generating prodrug for facile, safe, and efficient hydrogen delivery is vitally important for combined hydrogenochemotherapy but is still challenging. Here, targeting gastric cancer, a 2D magnesium boride nanosheet (MBN) is synthesized as a new type of acid‐responsive hydrogen‐releasing prodrug by an ultrasound‐assisted chemical etching route, which is used to realize hydrogenochemotherapy by combination of facile oral administration of polyvinylpyrrolidone (PVP)‐encapsulating MBN (MBN@PVP) pills with routine intravenous injection of doxorubicin (DOX). The MBN@PVP pill has high stability in normal tissues/blood environments as well as high gastric acid‐responsiveness with sustained release behavior, which matches well with its metabolism rate in the stomach in great favor of continuous and long‐term hydrogen administration. Hydrogenochemotherapy with DOX+MBN@PVP has remarkably prolonged the survival time of gastric tumor‐bearing mice by reducing the toxic side effects of chemotherapy. The mechanism for therapeutic synergy and side effect attenuation of hydrogenochemotherapy is discovered to be derived from the selectivity of hydrogen molecules in inhibiting aerobic respiration of gastric cells but activating aerobic respiration of normal cells including marrow mesenchymal stem cells and cardiac, hepatic, and splenic cells. A 2D magnesium boride nanosheetis developed as a new type of acid‐responsive hydrogen‐releasing prodrug to realize combined hydrogenochemotherapy, reducing toxic side effects, and enhancing anticancer outcomes of chemotherapy.