Recent advances in chemically controlled molecular hydrogen generation for biomedical applications

Molecular hydrogen (H₂), once regarded as a biologically inert gas, has recently emerged as a chemically active mediator with unique redox selectivity and excellent biocompatibility. In contrast to conventional gas administration, the biomedical efficacy of H₂ is fundamentally governed by its chemical generation pathways, reaction kinetics, and spatiotemporal controllability. Recent advances in chemistry-driven H₂ production—encompassing electrocatalytic, photocatalytic, sonocatalytic, piezocatalytic, chemical reaction–based, and biohybrid approaches—have enabled precise regulation of hydrogen generation at interfaces and within complex biological environments. These chemically controlled strategies enable selective regulation of highly reactive oxygen and nitrogen species. Beyond direct radical modulation, the generated hydrogen further regulates inflammatory signaling, mitochondrial homeostasis and immune responses, and ultimately remodels pathological microenvironments linked to inflammation, cancer, impaired wound healing and tissue degeneration. In this Review, we systematically summarize the chemical principles underlying H₂ bioactivity and critically analyze reaction mechanisms and material design strategies for controlled H₂ generation. Emphasis is placed on the chemical–biological coupling processes that translate molecular-scale reactions into macroscopic therapeutic outcomes. Finally, current challenges and future opportunities are discussed from a chemistry-centered perspective, highlighting the role of reaction engineering and chemical controllability in advancing hydrogen-based biomedical applications.