In-situ generation of hyperbaric hydrogen via crystallization-driven β-MgH₂ reservoirs for cancer-specific starvation therapy

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.