Metal-based hydrogen-generating therapeutic systems: From reactive chemistry to route-specific exposure and translational design.

Abstract

Molecular hydrogen (H2) has shown broad therapeutic relevance in oxidative injury, inflammation, metabolic dysfunction and tissue repair, yet its clinical translation remains limited by rapid diffusion, poor retention and a poorly defined dose-exposure relationship. Metal-based H2-generating systems offer an engineering strategy to produce or release H2 at pathological sites or material-tissue interfaces, where local exposure can be shaped by material design. This review reframes these platforms as material-formulation-route-indication systems rather than isolated material classes. The field now extends from classical metal hydrides to broader metal-containing platforms that generate or release H2 through hydrolysis, corrosion, electrochemical reactions or hydrogen storage-mediated release. Their therapeutic behavior is governed by route-specific exposure fields shaped by H2 release, accompanying reaction chemistry, formulation-defined compartments and tissue environments. Accordingly, route-oriented evaluation is essential because the same reactive core can produce distinct exposure profiles, safety boundaries and translational requirements across oral, local, vascular and implantable contexts. Mechanistically, H2-dependent redox and cytoprotective biology provides an important entry point, but therapeutic outcomes arise from a multi-effector local chemical milieu involving metal-derived species, coupled physicochemical changes and, in some platforms, external activation. Translational development therefore requires controlled materials engineering, route-specific exposure metrics, mechanism-matched validation, a PK/PD-like exposure-response framework adapted for reactive material systems and manufacturing strategies aligned with chemistry, manufacturing and controls (CMC) requirements. The field should advance toward route-specific, exposure-defined and mechanism-validated local reaction therapy.

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