In-situ generation of hyperbaric hydrogen via crystallization-driven β -MgH 2 reservoirs for cancer-specific starvation therapy

Abstract Molecular hydrogen (H2) shows promise for tumor treatment, whereas its therapeutic potential is seriously challenged by inadequate dosing along with unclear biological mechanisms. Herein, spurred on by the first successful report with high-pressure H2 inhalation administration, we develop a locally generated hyperbaric hydrogen platform by fabricating and leveraging crystalline β-phase magnesium hydride (MgH2) as reservoirs of superior hydrogen-releasing capacity for tumor starvation therapy. The as-synthesized particles allow crystallization-controlled, prolonged H2 generation lasting days upon reaction with water, which further achieve in-situ overpressure (> 1.8 atm) in response to the acidic tumor microenvironment (TME). We find that continuous exposure to single H2 of abundant supply can suppress energy metabolism in various types of tumor cells to inhibit proliferation and induce apoptosis. Moreover, the β-MgH2 reservoir yielding significant intratumoral H2 is demonstrated in vivo for both local and systemic administration models, of marked metabolic function disruption, and excellent antitumor efficacy without causing systemic toxicity. Mechanistically, we distinguish that locally enriched H2 plays dual roles of impairing tumor aerobic glycolysis via downregulating HIF-1α/GLUT1 axis, and eliciting mitochondrial damage associated with adenosine triphosphate (ATP) deprivation, which thereby synergistically block energy production for cancer anabolism. Collectively, our work delivers a proof of concept of "safe, local, long-acting" high-pressure hydrogen treatment modality to enable efficient cancer-selective starvation therapy.