Molecular Hydrogen Therapy: Mechanistic Foundations, Engineering of Delivery, and Clinical Translation

Abstract

Molecular hydrogen (H₂) has emerged as a potential therapeutic agent with antioxidant, anti-inflammatory, cytoprotective, metabolic, and immunomodulatory effects. Its rapid diffusion across biological membranes facilitates tissue penetration, whereas low aqueous solubility, rapid elimination, and limited retention restrict conventional delivery. This review integrates the mechanisms, delivery technologies, therapeutic applications, safety, and translational barriers of hydrogen therapy, with particular emphasis on the therapeutic advantages and added risks of materials-enabled local and sustained H₂ generation across disease settings. Mechanistically, H₂ attenuates highly reactive oxygen and nitrogen species and regulates nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant defenses, mitochondrial homeostasis, nuclear factor kappa B/NLR family pyrin domain-containing 3 (NF-κB/NLRP3)-mediated inflammation, programmed cell death, and host–microbial interactions. To overcome the limitations of inhalation and hydrogen-rich fluids, hydrogen-carrying nanosystems, in situ hydrogen-generating biomaterials, stimulus-responsive nanoplatforms, and biological production systems have been developed to improve localization and prolong H₂ availability. Experimental studies demonstrate therapeutic potential of H₂ in acute organ injury, cardiometabolic, neurological, respiratory, oncological, gastrointestinal, renal, and tissue-repair applications, but clinical evidence remains exploratory and most biomaterial-based systems remain limited to cellular and small-animal studies. The future development of hydrogen therapy should prioritize disease-specific indications and confirm H₂-dependent efficacy, while material-based nanosystems should demonstrate controllable H₂ generation, biodegradability, manufacturing reproducibility, and long-term safety in large-animal studies and well-controlled clinical trials.

Graphical abstract

Keywords

hydrogen therapy / molecular mechanisms / therapeutic applications / clinical translation / biomaterials

Introduction

Therapeutic gases occupy a distinctive position at the interface of pharmacology, physiology, and medical engineering. Oxygen, volatile anesthetics, and inhaled nitric oxide are established clinical products, whereas carbon monoxide, hydrogen sulfide, xenon, and molecular hydrogen have attracted increasing interest as signaling or cytoprotective agents. Molecular hydrogen (H₂) is particularly appealing because of its chemical simplicity, rapid tissue diffusibility, and favorable tolerability at the concentrations used in biomedical studies. The modern field is commonly traced to the observation that hyperbaric hydrogen induced regression of experimental tumors and, three decades later, to evidence that low-concentration H₂ attenuated oxidative injury after cerebral ischemia[1,2]. Subsequent experimental and early clinical studies have extended its potential applications to neurological, cardiovascular, metabolic, inflammatory, respiratory, renal, oncological, and exercise-related conditions (Figure 1)[3–6].

Despite the rapid expansion of the field, the molecular basis of hydrogen therapy remains incompletely understood. The initial selective-antioxidant hypothesis provided an intuitively appealing explanation for protection against oxidative injury, but direct scavenging alone is unlikely to account for the durable changes in gene expression, immune phenotype, metabolism, and tissue repair observed after transient, low-level H₂ exposure. H₂ has subsequently been associated with activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 signaling, inhibition of nuclear factor kappa B (NF-κB) and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, preservation of mitochondrial function, regulation of apoptosis and autophagy, modulation of lipid mediators, and changes in the intestinal microbiota[7–12]. These findings suggest that H₂ may act through amplification within redox-sensitive signaling networks rather than solely through the stoichiometric neutralization of reactive oxygen species (ROS). However, the initiating molecular targets have not been conclusively identified, experimental findings are not uniformly concordant, and context-dependent or biphasic effects have been reported. Distinguishing direct molecular interactions from downstream pathway associations is therefore essential for establishing a coherent mechanistic framework for hydrogen therapy.

Clinical translation is further complicated by the dependence of H₂ delivery on the systems used for its generation, storage, and administration. Unlike conventional small-molecule drugs, the administered dose of H₂ cannot be defined solely by the identity of the active agent. During inhalation, H₂ delivery is influenced by gas concentration, flow rate, breathing interface, inspired oxygen fraction, respiratory pattern, and treatment duration[13]. For hydrogen-rich water (HRW) and hydrogen-rich saline (HRS), preparation, storage, transfer, and the rapid dissipation of dissolved H₂ affect the amount available at administration. In material-based systems, local H₂ production and therapeutic availability depend on release kinetics, reactant supply, degradation behavior, and accessibility to the target tissue[14,15]. These variables directly affect dosing consistency, safety, and the interpretation of therapeutic outcomes, underscoring the clinical engineering requirements of hydrogen therapy. Clinical evidence also remains preliminary. Clinical investigations have evaluated inhaled H₂, hydrogen–oxygen mixtures, HRW, oral hydrogen-generating formulations, topical baths, and hydrogen-enriched infusions[16–19]. Although short-term tolerability and potential improvements in biomarkers or symptoms have been reported, most studies are limited by small cohorts, heterogeneous treatment protocols, and insufficient assessment of clinically meaningful endpoints. Successful translation will therefore require standardized characterization of delivery systems, reliable quantification of administered and tissue-available H₂, indication-specific efficacy assessment, and comprehensive safety evaluation.

Recent reviews have summarized the molecular mechanisms, therapeutic applications, clinical evidence, smart biomaterials, immunomodulatory effects, respiratory and oncological applications, and potential roles of H₂ in aging[13–15]. Building on this literature, this review integrates molecular mechanisms, delivery technologies, therapeutic applications, and translational considerations within a unified clinical engineering framework (Figure 2). Particular emphasis is placed on how the physicochemical properties of H₂ influence its biological activity and how delivery systems determine the localization, duration, and reproducibility of H₂ availability. Conventional administration methods are compared with hydrogen-carrying nanosystems, in situ hydrogen-generating biomaterials, stimulus-responsive platforms, and biological production systems, with a focus on the potential of material-based delivery to improve local and sustained H₂ generation. Evidence across major therapeutic areas is subsequently evaluated by integrating experimental studies of hydrogen-generating biomaterials with available clinical investigations of conventional H₂ administration. Finally, this review discusses safety and translational barriers and proposes priorities for confirming H₂-dependent efficacy, optimizing indication-specific delivery, characterizing biomaterial degradation and long-term safety, ensuring manufacturing reproducibility, and advancing promising systems toward large-animal studies and well-controlled clinical trials.

Molecular mechanisms of hydrogen therapy

Physicochemical basis of molecular hydrogen therapy

H₂ is a small neutral molecule. Its low molecular mass and nonpolar nature enable rapid diffusion across plasma and organelle membranes, providing access to the cytosol, mitochondria, and nucleus without requiring specific transporters. This broad subcellular accessibility allows H₂ to reach redox-active sites that may be less accessible to charged or larger antioxidant molecules. Despite its high diffusibility, H₂ has limited chemical reactivity under physiological conditions and does not function as an indiscriminate scavenger of ROS. Its low aqueous solubility, rapid diffusion and elimination, and limited tissue retention result in transient and delivery-dependent availability[3,5]. The biological effects of H₂ are therefore likely to involve both initial interactions with highly reactive species and subsequent regulation of redox-sensitive signaling, mitochondrial homeostasis, inflammation, and programmed cell death. These physicochemical properties provide the basis for the molecular mechanisms discussed below.

Direct interactions with reactive species

The classical antioxidant mechanism of hydrogen therapy is the selective neutralization of highly reactive oxygen and nitrogen species. H₂ has been proposed to react preferentially with hydroxyl radicals (•OH) and peroxynitrite (ONOO−), two highly cytotoxic species that can rapidly damage cellular lipids, proteins, and DNA[20,21]. In contrast, H₂ does not efficiently eliminate less reactive molecules such as superoxide, hydrogen peroxide, and nitric oxide, which also participate in physiological redox signaling. This selective action may therefore reduce oxidative damage without broadly suppressing the reactive species required for vascular regulation, immune defense, and cellular adaptation. Consistent with this mechanism, H₂ administration has repeatedly been associated with reduced lipid peroxidation, protein oxidation, DNA damage, and subsequent tissue injury in experimental models[11,12,22].

Direct radical scavenging is likely to be most relevant during acute oxidative bursts, such as those occurring during ischemia–reperfusion, inflammation, mitochondrial dysfunction, and toxic injury. However, the relatively low concentrations of H₂ achieved under many experimental and clinical conditions may be insufficient to neutralize all continuously generated reactive species. Moreover, changes in gene expression, mitochondrial function, and inflammatory responses can persist after H₂ itself is no longer detectable. Direct scavenging should therefore be regarded as an initial component of the antioxidant action of H₂ rather than a complete explanation for all of its biological effects. H₂ may additionally influence redox-sensitive molecules and activate endogenous antioxidant pathways.

Regulation of redox-sensitive signaling

The Nrf2/Keap1 pathway is a major redox-sensitive system regulated by H₂[23]. Under basal conditions, Keap1 promotes the ubiquitination and proteasomal degradation of Nrf2. Redox-dependent modification of Keap1 stabilizes Nrf2 and facilitates its nuclear translocation, where it binds to antioxidant response elements and induces cytoprotective genes, including heme oxygenase-1 (HO-1), NQO1 (NAD(P)H quinone oxidoreductase 1), and enzymes involved in glutathione metabolism. H₂ treatment has been associated with increased Nrf2 nuclear translocation and HO-1 expression in experimental models of acute lung injury, sepsis-associated encephalopathy, retinal injury, and ischemia–reperfusion[24–26]. Increased activities of superoxide dismutase, catalase, and glutathione peroxidase, together with preservation of intracellular glutathione, further support the ability of H₂ to strengthen endogenous antioxidant defenses.

H₂ also modulates the NF-κB/NLRP3 axis, which links oxidative stress to inflammatory signaling[27,28]. Excessive ROS production can activate the inhibitor of κB (IκB) kinase complex, promote IκB degradation, and facilitate NF-κB nuclear translocation. H₂ treatment suppresses this pathway and reduces the expression of inducible nitric oxide synthase, cyclooxygenase-2, chemokines, and proinflammatory cytokines. Reduced NF-κB-dependent priming may also inhibit NLRP3 inflammasome activation, caspase-1 cleavage, and interleukin‑1β (IL-1β) maturation[21,28,29]. These findings indicate that H₂ regulates cellular redox homeostasis by enhancing endogenous antioxidant defenses and limiting redox-sensitive inflammatory signaling.

Mitochondrial homeostasis and metabolic regulation

Mitochondrial dysfunction amplifies oxidative injury by increasing electron leakage and mitochondrial ROS production, leading to impaired membrane potential, respiratory-chain activity, and ATP synthesis. H₂ treatment has been reported to reduce mitochondrial oxidative stress, preserve membrane potential and ultrastructure, and maintain ATP production under inflammatory and ischemic conditions[30]. H₂ may also regulate mitochondrial dynamics through proteins such as mitofusin-2 and dynamin-related protein 1. During ischemia–reperfusion and other forms of acute stress, H₂ supports mitochondrial quality control by promoting PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and modulating autophagic pathways involving AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and transcription factor EB[31–34]. These effects facilitate the removal of damaged mitochondria and help maintain a functional mitochondrial network.

H₂ also influences cellular energy and lipid metabolism. In allergic airway inflammation, H₂ restored mitochondrial oxidative phosphorylation, improved respiratory-chain activity and ATP production, and reduced excessive reliance on glycolysis. Experimental and clinical investigations of metabolic disorders have further associated H₂ treatment with improved glucose regulation, insulin sensitivity, and hepatic lipid metabolism through pathways involving AMPK, silent information regulator 1 (SIRT1), and peroxisome proliferator-activated receptor α/peroxisome proliferator-activated receptor γ (PPARα/PPARγ)[11,18,35–37]. Metabolomic and lipidomic analyses also indicate changes in phospholipid turnover, amino-acid metabolism, and cellular energy pathways following H₂ treatment[38,39]. Collectively, these findings suggest that H₂ supports mitochondrial quality control and restores metabolic homeostasis rather than simply increasing mitochondrial activity.

Anti-inflammatory and immunomodulatory mechanisms

Downstream of its effects on redox-sensitive signaling, H₂ attenuates excessive innate immune activation. Suppression of NF-κB and NLRP3 inflammasome signaling reduces caspase-1 activation, IL-1β and interleukin‑18 (IL-18) maturation, and the production of tumor necrosis factor‑α (TNF-α), interleukin‑6 (IL-6), chemokines, and vascular adhesion molecules. These effects are associated with reduced leukocyte infiltration, tissue edema, and inflammatory injury in experimental models involving multiple organs[40–42]. H₂ also limits excessive neutrophil recruitment and activation, thereby reducing the release of ROS, proteases, and other tissue-damaging mediators. In macrophages and microglia, H₂ suppresses NF-κB/NLRP3-mediated inflammatory activation, reduces the production of TNF-α, IL-1β, and IL-6, and promotes the expression of anti-inflammatory and tissue repair-related mediators[22,43,44]. These effects limit sustained myeloid-cell activation and facilitate the resolution of inflammation and recovery of injured tissues.

H₂ may also regulate adaptive immune responses. Experimental studies and preliminary clinical investigations have reported changes in T-cell cytokine production, regulatory T-cell activity, and CD8⁺ T-cell function following H₂ treatment[45–47]. In the tumor microenvironment, some H₂-based interventions have been associated with reduced CD8⁺ T-cell exhaustion and preservation of antitumor effector activity. Collectively, these findings suggest that H₂ acts as a context-dependent immunomodulator that limits excessive inflammation while supporting immune functions involved in tissue repair, host defense, and antitumor responses.

Regulation of cell death, survival, and tissue repair

Regulation of cell survival is a major downstream consequence of the antioxidant, mitochondrial, and anti-inflammatory effects of H₂. In ischemic and inflammatory injury, H₂ increases the ratio of antiapoptotic to proapoptotic Bcl-2 family proteins, preserves mitochondrial membrane integrity, and limits cytochrome C release and caspase activation[48]. H₂ has also been associated with reduced activation of poly(ADP-ribose) polymerase-1 and improved survival of parenchymal and vascular cells[49]. In selected cancer models, H₂ exerts the opposite effect by suppressing prosurvival signaling and promoting mitochondrial apoptosis in tumor cells[50–52]. Its influence on apoptosis therefore depends on the redox state, metabolic characteristics, and survival pathways of the affected cell.

H₂ also regulates pyroptosis and ferroptosis. In inflammatory and ischemic injury, suppression of the NLRP3/caspase-1/gasdermin D (GSDMD) pathway reduces pyroptotic membrane disruption and the release of IL-1β and IL-18. Conversely, activation of pyroptosis has been implicated in the inhibitory effect of H₂ on endometrial cancer cells[30,52]. In neural injury, H₂ reduces lipid peroxidation and preserves antioxidant defenses associated with ferroptosis, thereby limiting iron-dependent neuronal death[32,53]. These findings further demonstrate that H₂ regulates cell-death programs according to disease and cellular context rather than producing a uniform prosurvival effect.

By limiting oxidative injury, excessive inflammation, and the loss of viable cells, H₂ may create a cellular environment favorable for tissue repair. Experimental studies have associated H₂ treatment with improved endothelial survival, microvascular perfusion, re-epithelialization, extracellular matrix remodeling, and wound closure[54–56]. Local hydrogen-generating biomaterials may enhance these effects by maintaining H₂ availability within wounds or ischemic tissues[14,15]. The reparative activity of hydrogen therapy therefore appears to result from the coordinated preservation of viable tissue, resolution of inflammation, and restoration of vascular and structural integrity.

Gut microbiota-mediated mechanisms

The gut microbiota is both an endogenous source of H₂ and a potential target of hydrogen therapy. Microbial fermentation of dietary carbohydrates generates H₂ in the intestinal lumen, where it can be further consumed by methanogens, sulfate-reducing bacteria, and acetogens. The balance between H₂-producing and H₂-consuming microorganisms influences the luminal redox environment and microbial metabolite production. Hydrogen-related effects in intestinal inflammation, metabolic disease, colorectal cancer, and neurological disorders may therefore involve interactions among exogenous H₂, endogenous microbial hydrogen metabolism, and host signaling pathways[10,11]. Experimental studies have shown that HRW and other H₂-based interventions can alter microbial composition, increase potentially beneficial or short-chain fatty acid-producing bacteria, and reduce the abundance of inflammation-associated taxa[57]. These changes have been accompanied by improved tight-junction integrity, reduced intestinal permeability and circulating lipopolysaccharide, and attenuation of inflammatory signaling along the gut–liver and gut–brain axes[11]. Microbiota modulation may consequently contribute to both local intestinal protection and systemic effects of hydrogen therapy, although its causal contribution relative to the direct actions of H₂ on host tissues remains to be established.

Taken together, the available evidence supports a network-based rather than a single-target mechanism of hydrogen therapy (Figure 3). H₂ may initially attenuate highly reactive oxygen and nitrogen species, followed by regulation of Nrf2-dependent antioxidant defenses, mitochondrial homeostasis, NF-κB/NLRP3-mediated inflammation, programmed cell death, and host–microbial interactions. The direction and magnitude of these effects depend on the baseline redox state, cell type, disease stage, and biological context, with sex, age, diet, microbiota, oxygen tension, and comorbidities acting as potential modifiers. The context-dependent effects of H₂ require consideration when it is combined with anticancer therapies that exert cytotoxic effects partly through ROS generation. In a cisplatin-based model, H₂ protected normal tissues without compromising antitumor activity[58]. However, this finding may not extend to other therapeutic agents or treatment regimens. H₂ is therefore more appropriately regarded as a context-dependent modulator of redox homeostasis and cellular stress responses than as a universal ROS scavenger.

Hydrogen administration and materials-enabled delivery systems

Conventional administration modalities

Conventional administration of H₂ includes gas inhalation, ingestion of HRW, injection of HRS, and topical or extracorporeal application. These approaches differ in convenience, controllability, anatomical distribution, and suitability for acute or repeated treatment (Table 1). Across these modalities, the nominal H₂ dose alone does not adequately describe biological exposure, because the concentration–time profile within the target tissue is jointly determined by delivery efficiency, diffusion, tissue retention, and clearance. The following sections therefore examine how route- and platform-specific engineering parameters regulate the spatial and temporal availability of H₂.

Hydrogen gas inhalation

Inhalation provides rapid systemic delivery and allows the administered H₂ concentration and treatment duration to be adjusted. Studies have used low-concentration H₂ in air, hydrogen–oxygen mixtures generated by electrolysis, and higher concentrations under controlled conditions[19,59]. The concentration reaching the patient is influenced by gas flow, breathing interface, air entrainment, leakage, respiratory pattern, and concomitant oxygen therapy. Clinical protocols should therefore report the gas source, concentration measured at the patient interface, flow rate, duration, and treatment frequency. Because hydrogen is flammable within defined concentration ranges in air, ventilation, leak detection, electrical safety, and separation from ignition sources are essential components of inhalation systems.

Hydrogen-rich water

HRW is noninvasive, inexpensive, and suitable for repeated outpatient administration. It has been investigated in metabolic, neurological, exercise-related, gastrointestinal, and inflammatory conditions[18,60–62]. HRW can be produced by electrolysis, pressurized dissolution, magnesium-based reactions, or hydrogen-generating tablets. However, dissolved H₂ escapes rapidly after preparation, and its concentration is affected by storage time, temperature, headspace, and container material. Studies should report the H₂ concentration at the time of consumption rather than relying only on the initial concentration or manufacturer specification. In addition to transient systemic delivery, HRW may exert local effects on the intestinal mucosa and gut microbiota.

Hydrogen-rich saline and injectable formulations

HRS has been used predominantly in preclinical models of ischemia–reperfusion, neurological injury, renal injury, and inflammation[36,42,63–65]. Injection provides a defined fluid volume and bypasses gastrointestinal administration, but dissolved H₂ may be lost during storage, syringe preparation, and infusion. Preparation method, final H₂ concentration, sterility, container permeability, and compatibility with infusion systems should therefore be documented. Because of its invasiveness, HRS may be more appropriate for acute care, perioperative treatment, or organ preservation than for long-term administration.

Topical and extracorporeal applications

Topical administration includes hydrogen-rich bathing, wound irrigation, ocular formulations, and direct application to the skin or mucosa. These approaches can concentrate H₂ near the treatment site while limiting systemic distribution and have been investigated in skin, wound, microcirculatory, and ocular conditions. Interpretation requires control of H₂ concentration, contact time, temperature, pH, and electrolysis-related by-products[66]. Extracorporeal approaches, such as hydrogen-enriched dialysis and organ perfusion, similarly permit regional treatment through an existing fluid circuit but require validation of gas transfer, bubble removal, hemocompatibility, sterilization, and device safety[67].

Although conventional administration provides clinically accessible routes for hydrogen therapy, it offers limited control over H₂ retention and spatial distribution. Inhaled H₂ is rapidly eliminated, dissolved H₂ readily escapes from aqueous formulations, and neither approach preferentially concentrates H₂ within a target lesion. These limitations are particularly relevant to solid tumors, ischemic tissues, chronic wounds, and localized inflammatory diseases, where sustained or site-specific delivery may be required. Materials-enabled systems address these challenges by either loading preformed H₂ into a carrier for subsequent release or generating H₂in situ through chemical, catalytic, or biological reactions[15,68]. Such systems can prolong local H₂ availability, respond to pathological microenvironments or external stimuli, and integrate hydrogen delivery with imaging and complementary therapeutic functions[69,70].

Hydrogen-carrying and preloaded release nanosystems

Hydrogen-carrying systems physically dissolve, adsorb, or store preformed H₂ before administration. Representative platforms include hydrogen-containing micro- or nanobubbles, perfluorocarbon nanoemulsions, porous nanoparticles, metal-organic frameworks, and metal hydrides. Perfluorocarbon formulations have a high affinity for gases and can retain H₂ within injectable nanodroplets, whereas microbubbles and nanobubbles can facilitate local release and ultrasound monitoring[71]. These systems have been investigated for myocardial ischemia–reperfusion injury, tumors, and inflammatory diseases (Table 2).

Palladium hydride is one of the most widely studied solid hydrogen carriers (Figure 4)[72]. Hydrogen atoms can occupy interstitial sites within the palladium lattice and subsequently be released through diffusion or external stimulation. Nanostructural engineering can increase hydrogen-loading capacity and regulate the release rate, while integration with porous frameworks, polymers, or hydrogels can improve dispersion and tissue retention. Palladium-hydride systems have been evaluated in models of neurodegeneration, atherosclerosis, cancer, and infected wounds[72–76]. The principal advantages of preloaded carriers are immediate H₂ availability and the absence of a continuous chemical reaction with surrounding tissues. Their limitations include restricted payload, premature leakage, incomplete release, and potential persistence of nondegradable carrier materials.

In situ hydrogen-generating biomaterials

In situ generating systems produce H₂ after administration by reacting with water, protons, or other substrates in the biological environment (Figure 5). This approach avoids the limited loading capacity of pre-formed carriers and can provide more sustained local production. The rate and duration of H₂ generation can be regulated through material composition, particle size, surface coatings, porosity, encapsulation, and the availability of the reactive substrate.

Water- and proton-responsive biomaterials

Magnesium, magnesium hydride, silicon-based materials, metal silicides, borides, borohydrides, and ammonia-borane formulations can generate H₂ through reactions with water or protons. Magnesium-based systems are particularly attractive because magnesium is biodegradable and its reaction with water or acidic fluids produces H₂ while releasing Mg²⁺[77–79]. Silicon and silicon-hydride nanoparticles generally react more slowly and can provide prolonged hydrogen generation[80,81]. Boride- and borohydride-based materials offer relatively high hydrogen yields but require careful control of reaction rate and by-product safety[82,83].

Unmodified reactive particles may generate H₂ too rapidly or become passivated before reaching the target tissue. Polymeric matrices and hydrogel-based devices can protect hydrogen-generating components from premature reaction with water and enable controlled, sustained local H₂ production. These strategies have been evaluated in experimental models of diabetic wound healing and ischemia–reperfusion injury[55,84]. Their performance should be evaluated using the measured H₂ generation rate and duration under physiologically relevant conditions rather than theoretical hydrogen yield alone.

Microenvironment-responsive nanosystems

Disease-associated microenvironments provide endogenous signals for selective H₂ generation. The acidic microenvironments of solid tumors and inflammatory lesions can accelerate proton-dependent H₂-generating reactions or dissolve acid-labile coatings, thereby exposing reactive hydrogen-producing components[85,86]. Enzyme-, ROS-, and redox-responsive gates can similarly expose a hydrogen precursor or activate a catalyst after the material reaches the lesion[87,88]. Surface ligands such as hyaluronic acid or folate may further enhance accumulation in cells expressing the corresponding receptors. Microenvironment-responsive systems reduce premature H₂ release and increase spatial selectivity without requiring external equipment. However, pH, enzyme activity, perfusion, and substrate availability vary within and between lesions, leading to heterogeneous hydrogen generation. The carrier may also exert H₂-independent effects through ion release, local pH changes, catalytic activity, or structural support. These contributions should be evaluated using an unloaded carrier or a non-H₂-generating analogue matched, for composition, particle size, surface chemistry, administration procedure, and degradation behavior where feasible. Separate controls for relevant ions, reaction products, and local pH changes may also be required to determine whether these factors contribute independently to the observed therapeutic effects.

Externally triggered nanoplatforms

External energy enables temporal and spatial control over H₂ production or release. Light-responsive systems generate H₂ through photocatalytic reactions or release it from hydrogen-storing materials[89,90]. Near-infrared (NIR) light penetrates tissue more effectively than ultraviolet or visible light and has been used to activate palladium hydrides, semiconductor heterostructures, upconversion nanoparticles, and hydrogen-containing precursors. A biomimetic upconversion nanoreactor has been developed to achieve NIR-triggered local H₂ generation and attenuate oxidative stress and tau hyperphosphorylation in an Alzheimer’s disease mouse model[91]. Nevertheless, optical activation remains limited by tissue absorption and scattering, which restrict light delivery to deep or anatomically inaccessible lesions. Ultrasound-responsive systems may overcome this limitation by producing H₂ in deeper tissues through acoustic cavitation, sonocatalysis, or piezoelectric reactions[78,92,93]. Electrical and magnetic stimulation have also been investigated for electrochemical H₂ generation and remotely controlled release[94,95]. Externally triggered nanoplatforms designed for in situ H₂ generation are particularly well suited to localized lesions where activation and treatment can be guided by imaging. Some systems combine H₂ delivery with photoacoustic, magnetic resonance, fluorescence, or ultrasound imaging and integrate hydrogen therapy with photothermal therapy, photodynamic therapy, chemotherapy, or immunotherapy. Related gas-responsive nanomedicines also provide transferable principles for stimulus-gated release. However, heat, ROS, cavitation, electrical stimulation, and co-delivered agents may contribute to the observed therapeutic effects. Factorial controls are therefore required to distinguish the effects of H₂ from those of the carrier, triggering energy, and accompanying treatment.

Biological hydrogen-generating platforms

Biological systems seek to generate H₂ through endogenous or engineered metabolic pathways. Strategies include stimulation of hydrogen-producing intestinal microorganisms, administration of selected probiotics or prebiotic substrates, and use of engineered bacteria, microalgae, or hydrogenase-containing systems. Because living systems can replicate and respond to their environment, they may sustain H₂ production for longer periods than conventional formulations or reactive particles. Inflammatory intestinal diseases, particularly ulcerative colitis, are attractive targets for material-based H₂ therapy because orally or rectally administered hydrogen-generating systems can produce H₂ directly within the intestinal lumen, thereby increasing its availability at the injured mucosa[10,96,97]. Biological production is nevertheless influenced by diet, colonization efficiency, competition with resident microorganisms, hydrogen-consuming species, and host immunity. Engineered organisms introduce additional concerns related to genetic stability, environmental containment, and unintended persistence. Therapeutic development therefore requires quantitative confirmation of hydrogen production together with appropriate biosafety controls. At present, these approaches remain less controllable than inorganic or polymer-based systems and are predominantly at an early experimental stage.

Across these delivery platforms, therapeutic performance is determined not only by the total amount of H₂ loaded or generated, but also by how engineering parameters shape its spatial and temporal availability. For conventional administration, the delivered concentration, flow rate, treatment duration, formulation handling, and loss during administration govern systemic exposure and subsequent washout. In preloaded carriers, H₂-loading capacity, particle size, porosity, carrier permeability, colloidal stability, and tissue retention determine the balance between rapid release and prolonged local exposure. For in situ H₂-generating systems, material composition, reactive surface area, passivation, coating thickness, hydrogel structure, and local substrate availability regulate the generation rate and diffusion of H₂. In stimulus-responsive platforms, the activation threshold, tissue penetration, intensity, focal volume, and duration of the applied stimulus further define where and when H₂ is produced. These parameters determine the local concentration, exposure duration, and spatial gradient of H₂, thereby influencing its temporal overlap with oxidative stress, inflammatory signaling, mitochondrial dysfunction, and tissue-repair processes. Consequently, platforms producing similar total amounts of H₂ may induce different biological responses and therapeutic outcomes. Their performance should therefore be evaluated by correlating physiologically measured H₂ release or generation profiles with target-tissue exposure, mechanistic readouts, and functional outcomes, rather than by theoretical hydrogen yield alone.

Attribution of therapeutic efficacy is particularly important for engineered H₂ delivery systems because the carrier, its degradation products, and any activating stimulus may produce biological effects independently of H₂. For preloaded systems, H₂-loaded carriers should be compared with otherwise matched H₂-depleted or unloaded carriers. For reactive materials, non-H₂-generating analogues and controls containing the relevant ions or reaction products should be used to distinguish H₂-mediated effects from changes caused by material degradation or local pH. Catalytic and externally triggered platforms additionally require trigger-only and carrier-plus-trigger controls to account for intrinsic catalytic activity, heat, ROS generation, cavitation, light exposure, or electrical stimulation. Hydrogels and biological platforms should similarly control for scaffold-mediated tissue repair and non-H₂-related microbial or metabolic effects. When H₂ delivery is combined with another treatment, a factorial design should independently vary H₂ generation and the accompanying intervention to identify their individual and interactive contributions. Evidence for H₂-dependent efficacy is strengthened when H₂ generation is verified within the target tissue, its magnitude and timing are associated with mechanistic and functional outcomes, and comparable effects are reproduced using an independent H₂-delivery modality. If these contributions cannot be experimentally separated, the observed benefit should be attributed to the complete therapeutic platform rather than to molecular hydrogen alone.

Therapeutic applications of molecular hydrogen

The therapeutic applications of H₂ encompass conventional administration, materials-enabled local delivery, and biologically or externally triggered hydrogen generation. Evidence ranges from cellular and animal models to exploratory clinical studies, and findings obtained at different stages of development should not be regarded as interchangeable. In particular, the efficacy of a locally implanted hydrogen-generating material cannot be extrapolated directly to inhalation or HRW, because the administered product, anatomical distribution, accompanying material effects, and intended clinical setting differ substantially.

Acute organ injury and ischemia–reperfusion

Ischemia–reperfusion injury is characterized by an abrupt increase in ROS production, mitochondrial dysfunction, sterile inflammation, microvascular impairment, and cell death during early reperfusion, providing multiple mechanistic targets for H₂ intervention. Inhaled H₂, HRS, and HRW have reduced tissue injury in experimental models involving the brain, heart, liver, kidney, intestine, lung, skin flap, and limb[33–35,60,61,63,98–100]. These protective effects have been associated with preservation of mitochondrial function, activation of Nrf2/HO-1 signaling, suppression of NF-κB/NLRP3-mediated inflammation, and improvement of microvascular perfusion. Materials-based systems have subsequently been developed to increase local H₂ availability within ischemic tissues. Hydrogen-containing microbubbles and perfluorocarbon nanoemulsions have enabled image-guided H₂ delivery to the reperfused myocardium[71], whereas reactive nanoparticles and injectable hydrogels have been investigated for sustained H₂ generation in ischemic or poorly perfused tissues[84]. However, these material-based approaches remain predominantly at the small-animal stage.

Clinical evaluation has so far focused on inhaled H₂ and hydrogen-enriched intravenous fluids rather than material-based delivery. Early studies in patients with acute cerebral ischemia or post-cardiac-arrest syndrome have primarily demonstrated the feasibility and short-term safety of H₂ administration, while evidence for improved survival and functional neurological recovery remains preliminary[101–105]. Future trials should determine whether H₂ provides additional benefit when administered at clinically realistic time points and combined with established interventions such as reperfusion therapy, temperature control, ventilation, and hemodynamic support. The predominance of prophylactic or immediate-treatment protocols in animal studies limits their clinical extrapolation, because H₂ treatment in patients is generally initiated after an uncertain ischemic interval and must be integrated with reperfusion and other acute-care interventions.

Cardiovascular and metabolic diseases

Experimental cardiovascular studies indicate that H₂ attenuates oxidized low-density lipoprotein (ox-LDL)-induced oxidative stress and inflammatory signaling in endothelial cells, reduces lipid oxidation and vascular lipid accumulation in atherosclerotic models, and limits myocardial injury, fibrosis, and adverse remodeling after myocardial infarction[42,106,107]. Protective effects have been reported in models of hypertension, atherosclerosis, myocardial infarction, cardiac arrest, and myocardial ischemia–reperfusion[34,108,109]. These effects involve improved endothelial signaling, reduced lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and NF-κB activity, preservation of mitochondrial quality control, and attenuation of fibrosis.

Material-based H₂ delivery platforms offer a promising strategy for localized treatment of focal cardiovascular lesions. Hydrogen-loaded perfluorocarbon nanoemulsions have been developed for image-guided treatment of myocardial ischemia, whereas palladium-hydride nanopocket structures and nanozymes provide sustained H₂ release and antioxidant activity in experimental atherosclerosis[71,76]. Compared with systemic inhalation or HRW, these systems may concentrate H₂ within ischemic myocardium or vascular lesions, but their biodistribution, clearance, and long-term vascular safety require further evaluation.

Clinical studies in patients with impaired glucose regulation, type 2 diabetes, metabolic syndrome, or hepatic steatosis have reported improvements in selected measures of glucose metabolism, lipid profiles, inflammation, and liver function following HRW consumption or H₂ inhalation[18,37,62,110]. However, study populations, treatment schedules, background therapies, and outcome measures vary considerably. Current evidence supports further indication-specific clinical investigation but does not establish prevention of cardiovascular events or durable control of metabolic disease. In addition, in chronic cardiometabolic disorders, the clinical significance of modest changes in surrogate biomarkers remains uncertain, particularly when background medication, diet, disease duration, and treatment adherence are not adequately controlled.

Neurological and neurodegenerative diseases

H₂ has been extensively studied in neurological models because oxidative stress, mitochondrial dysfunction, neuroinflammation, and blood-brain barrier injury contribute to both acute and chronic neurological disorders. H₂ administration has reduced neuronal injury in models of neonatal hypoxia-ischemia, ischemic stroke, subarachnoid hemorrhage, traumatic brain injury, neuropathic pain, and neurodegeneration[12,22,25,49,111,112]. Materials-enabled delivery may prolong H₂ availability within the central nervous system. Palladium-hydride nanoparticles produced sustained hydrogen release and improved cognitive and pathological outcomes in an experimental Alzheimer’s disease model[72]. Silicon-based hydrogen-generating particles, hydrogels, and other nanosystems have also been explored for local or prolonged neuroprotection[81]. These strategies may overcome the rapid elimination of inhaled or dissolved H₂, although invasive administration and persistence of inorganic materials remain important limitations.

Clinical evidence remains limited and inconsistent across neurological indications. Small open-label studies in Alzheimer’s disease have reported cognitive or biomarker changes, but do not establish disease-modifying efficacy[103]. A randomized pilot trial of H₂ inhalation in Parkinson’s disease did not demonstrate significant clinical benefit despite acceptable safety[59]. Preliminary clinical studies in acute ischemic stroke indicate that inhaled H₂ and intravenously administered hydrogen-enriched fluids are feasible and generally well tolerated, and exploratory findings include favorable changes in magnetic resonance imaging (MRI) indices and neurological or functional scores, although therapeutic efficacy remains to be established[113]. Acute neuroprotection and chronic neurodegeneration should therefore be developed as separate indications with different treatment schedules, study populations, and outcome measures. Benefits observed in acute neuronal injury or early-stage experimental disease should not be extrapolated directly to established neurodegeneration, in which irreversible neuronal loss and heterogeneous regional exposure may limit therapeutic responsiveness.

Respiratory and critical-care applications

The respiratory tract is directly accessible to inhaled H₂, making pulmonary disease one of the most practical applications of conventional administration. Experimental studies have shown that H₂ attenuates acute lung injury induced by sepsis, hyperoxia, and mechanical ventilation. Reported effects include reduced pulmonary inflammation and edema, protection against epithelial apoptosis, preservation of mitochondrial function, and improved gas exchange[114].

Materials-assisted H₂ strategies have recently been explored for pulmonary diseases. Intratracheally administered hydrogenated silicene/poly(lactic-co-glycolic acid) (SiH/PLGA) nanosponges enable sustained local H₂ generation in experimental acute lung injury, whereas an ammonia-borane-loaded microalgal nanosystem provides infection-responsive systemic H₂ release in septic mice[115,116]. In parallel, aerosolized lipid nanoparticles have been co-delivered with inhaled H₂ to enhance pulmonary RNA delivery in experimental fibrosis[117]. Such platforms may combine hydrogen generation with oxygen production, anti-inflammatory activity, or targeted delivery. However, clinical translation of these platforms requires rigorous evaluation of intrapulmonary particle deposition and clearance, carrier-associated inflammatory and immune responses, and compatibility with mechanical ventilation and other respiratory-support modalities.

Clinical studies in patients with asthma or chronic obstructive pulmonary disease (COPD) have associated H₂-containing gas inhalation with reductions in airway inflammatory markers or improvements in respiratory symptoms[118]. A multicenter randomized trial in acute COPD exacerbation reported greater symptom improvement with a hydrogen–oxygen mixture than with oxygen alone[19]. Hydrogen–oxygen mixtures were also evaluated during the COVID-19 pandemic, although nonrandomized designs, patient selection, and changing standards of care limit interpretation[16,119]. A pilot HRW study in patients with long COVID reduced fatigue but not dyspnea[120]. Future studies should distinguish respiratory support from disease-modifying treatment and prioritize ventilator-free days, functional recovery, hospitalization, and mortality over isolated biomarker changes.

Cancer therapy and supportive oncology

Experimental studies indicate that H₂-based interventions can exert context-dependent antitumor effects by suppressing tumor-cell proliferation, inducing regulated cell death, altering tumor metabolic states, and remodeling the stromal immune microenvironment[121,122]. These findings differ from the cytoprotective effects observed in normal tissues and may reflect the abnormal redox state, metabolic dependence, and survival signaling of tumor cells. Cancer is also the most extensively studied application of materials-enabled hydrogen therapy. Acid-responsive magnesium, magnesium diboride, iron, and ammonia-borane-loaded mesoporous silica systems can generate H₂ in acidic tumor or gastric microenvironments, whereas palladium hydrides permit NIR-controlled release of stored H₂ and semiconductor or piezoelectric nanoplatforms enable light- or ultrasound-driven H₂ production[75,79,80,83,123–125]. These systems have been combined with photothermal therapy, photodynamic therapy, chemotherapy, catalytic therapy, and immunotherapy. Local hydrogen production may improve tumor selectivity and modulate hypoxia, mitochondrial metabolism, lipid synthesis, or immune-cell exhaustion. However, tumor suppression often results from several simultaneous interventions, and the specific contribution of H₂ should be established using appropriate carrier, trigger, and reaction-product controls.

Clinical evidence is limited to small studies, case series, and observational reports. H₂ inhalation has been investigated in patients with advanced non-small-cell lung cancer, and a real-world series reported outcomes in patients with heterogeneous advanced cancers[46,47]. These studies cannot separate the effects of H₂ from concurrent chemotherapy, targeted therapy, immunotherapy, differences in patient selection, or the natural course of disease. Supportive oncology may represent a more immediate application. HRW has been associated with preservation of liver function during colorectal cancer chemotherapy, while animal studies suggest reduced cisplatin- and doxorubicin-related toxicity[126,127]. H₂ inhalation has also been explored for radiation-associated bone-marrow injury[128]. Because several anticancer treatments depend on ROS generation, tumor control and normal-tissue protection must be evaluated simultaneously. H₂ should currently be considered an experimental adjunct rather than an alternative to established cancer therapy.

Gastrointestinal, hepatic, and renal diseases

The gastrointestinal tract is well suited to both HRW and orally administered hydrogen-generating materials. Conventional H₂ administration has reduced oxidative stress, epithelial injury, NF-κB/NLRP3 activation, and barrier dysfunction in models of intestinal ischemia–reperfusion and inflammatory bowel disease[10,41,61,129,130]. Changes in tight-junction proteins, microbial composition, and short-chain fatty acids suggest that both direct mucosal effects and microbiota-mediated mechanisms contribute.

Enteric-coated magnesium-hydride microcapsules and silicon-based nanoparticles have been designed to generate H₂ selectively within the intestine. By protecting reactive materials during gastric transit and controlling their activation in the distal bowel, these systems prolong local hydrogen production and have improved colitis and mucosal injury in animal models[97,131]. Hydrogen-generating hydrogels, reactive nanomaterials, and biohybrid H₂-producing systems have likewise been investigated for localized treatment of experimental intestinal inflammation[132,133]. These approaches provide clearer anatomical targeting than inhalation but remain at the preclinical stage. In liver disease, H₂ has reduced ischemia–reperfusion injury, toxic damage, steatosis, endotoxemia, and gut-liver inflammatory signaling[31,36,134]. A randomized clinical study of hydrogen–oxygen inhalation in nonalcoholic fatty liver disease reported improvements in selected outcomes[37], although larger studies with standardized lifestyle management and imaging or histological endpoints are required. Renal studies have addressed acute ischemic injury, oxalate-induced damage, chronic kidney disease, chemotherapy-related nephrotoxicity, and dialysis-associated fibrosis[100,135]. Most evidence is derived from animal models treated with HRS or HRW. Initial clinical evaluation of renal applications may be most feasible in settings with predictable treatment windows, such as surgery, transplantation, contrast administration, and dialysis.

Aging, musculoskeletal disorders, and tissue repair

H₂ has been proposed to influence mitochondrial dysfunction, chronic inflammation, impaired autophagy, cellular senescence, genomic stress, and dysbiosis associated with aging[23]. Small studies in older adults have reported changes in selected metabolic, inflammatory, or functional measures. However, these findings do not establish an anti-aging effect, and aging itself does not constitute a clearly defined therapeutic indication. Exercise and rehabilitation studies have reported variable effects on blood lactate, perceived exertion, fatigue, recovery, and physical performance[6,136–138]. Differences in sample size, training status, exercise protocol, and HRW concentration contribute to heterogeneity. Current evidence suggests that H₂ may modify selected fatigue or recovery outcomes under particular conditions, but does not support its use as a general performance-enhancing intervention.

Local hydrogen delivery may have greater relevance to musculoskeletal disease and tissue repair. H₂ has reduced inflammation and tissue damage in experimental osteoarthritis, ischemic muscle injury, skin disease, and chronic wounds[139,140]. Hydrogen-generating hydrogels, magnesium-based materials, palladium-hydride nanostructures, and catalytic wound dressings can maintain local H₂ production while providing structural support or antibacterial activity[14,68,69]. Such multifunctional systems have accelerated wound closure and improved tissue regeneration in animal models, but should ultimately be compared with contemporary wound care, rehabilitation, or anti-inflammatory treatment.

Taken together, current evidence supports the therapeutic potential of H₂ across acute organ injury, cardiometabolic disease, neurological and respiratory disorders, cancer, gastrointestinal, hepatic and renal diseases, and tissue repair. However, the maturity of evidence differs substantially among delivery modalities. Conventional administration through inhalation, HRW, or HRS has progressed from extensive preclinical investigation to exploratory clinical evaluation, with generally acceptable short-term feasibility but limited evidence of confirmatory efficacy. Hydrogen-carrying nanosystems and in situ H₂-generating biomaterials may improve localization, prolong H₂ availability, and enable stimulus-responsive treatment, although most remain at the cellular or small-animal stage.

Interpretation of this evidence is complicated by variation in administration route, H₂ dose, treatment timing, formulation stability, disease severity, experimental model, and outcome assessment. Preclinical studies frequently use prophylactic or immediate treatment in young, otherwise healthy animals, whereas clinical administration generally begins after disease onset in heterogeneous patients receiving standard care. Target-tissue H₂ exposure is also rarely quantified, and dose–response relationships remain poorly defined; consequently, a higher nominal dose or theoretical H₂ yield does not necessarily produce greater therapeutic benefit. The required exposure profile may also differ by disease, ranging from treatment synchronized with acute reperfusion injury to repeated or sustained delivery for chronic disorders. Advanced irreversible tissue damage and interactions with ROS-dependent anticancer treatments may further limit or modify efficacy.

Future studies should therefore standardize H₂ preparation, administration, exposure measurement, and outcome reporting while adopting clinically realistic models and treatment schedules. Appropriate consideration of age, sex, comorbidities, randomization, blinding, validated endpoints, and independent replication will be essential for improving reproducibility. Material-based approaches should be prioritized for indications in which localized or sustained H₂ delivery offers a clear advantage, such as solid tumors, ischemic lesions, intestinal inflammation, and chronic wounds. Their development should optimize H₂-generation kinetics and tissue targeting, establish carrier and degradation-product safety, and distinguish H₂-dependent effects from those of the material or activating stimulus. Material-based platforms should also be directly compared with conventional H₂ administration and standard treatment in relevant large-animal models.

Safety and translational barriers in hydrogen therapy

Although molecular hydrogen is generally considered to have a favorable safety profile, the safety of hydrogen therapy depends on the complete treatment system rather than H₂ alone. Conventional administration, hydrogen-carrying nanosystem, in situ hydrogen-generating materials, and biological production platforms introduce different risks. In material-based therapy, carrier composition, degradation products, hydrogen-generation kinetics, tissue distribution, and accompanying physical or chemical effects must therefore be evaluated together with the biological effects of H₂.

Biological safety and treatment interactions

H₂ is not known to be metabolized into reactive or toxic products in mammalian tissues and is rapidly eliminated, primarily through exhalation. Clinical studies involving inhaled H₂, HRW, HRS, and hydrogen–oxygen mixtures have generally reported acceptable short-term tolerability[17–19,59]. However, most studies include relatively small populations and limited follow-up. Evidence remains insufficient for prolonged or repeated treatment, high H₂ concentrations, and administration in children, pregnant individuals, or patients with severe organ dysfunction.

The biological effects of H₂ may also interact with established treatments. Its antioxidant and cytoprotective properties could protect normal tissues during chemotherapy or radiotherapy but might modify treatments that depend on ROS generation. H₂ has reduced cisplatin-associated nephrotoxicity in animal models without compromising antitumor efficacy, but this result cannot be generalized to other drugs or tumor types. Similar considerations apply to antimicrobial defense, immune activation, and exercise-induced adaptive signaling. Combination studies should therefore evaluate both disease control and treatment-related toxicity rather than assuming that attenuation of oxidative stress is uniformly beneficial.

Biosafety and quality control of hydrogen-releasing biomaterials

The favorable biological safety of free H₂ does not establish the safety of a hydrogen-carrying or hydrogen-generating material. Reactive magnesium-, silicon-, iron-, boride-, and hydride-based systems may alter local pH or release biologically active ions. Some degradation products, such as Mg²⁺ or soluble silicon species, may contribute to angiogenesis, bone regeneration, or tissue repair, but excessive local accumulation may also disturb cellular homeostasis. Poorly degradable metals such as palladium present a different concern because nanoparticles or released ions may persist in the liver, spleen, kidney, or other tissues[70–72].

Material assessment should include particle size, morphology, surface chemistry, aggregation, residual reagents, sterility, endotoxin, degradation rate, ion release, biodistribution, clearance, immunogenicity, and local tissue responses. Externally triggered systems require additional evaluation of heat, ROS, cavitation, electrical stimulation, or mechanical effects generated by the activating energy. Engineered bacteria, probiotics, and microalgae introduce concerns related to colonization, genetic stability, immune recognition, and unintended persistence. The effects of H₂ should therefore be distinguished from those of the carrier, released ions, reaction products, triggering stimulus, and other therapeutic components.

Reproducible manufacturing is essential for the translation of material-based H₂ therapy. Variations in crystal structure, catalyst content, porosity, surface coating, and particle size can markedly affect H₂ yield and release kinetics. Quality-control testing should therefore verify material identity and characterize H₂-loading or generation capacity, release rate and duration, stimulus responsiveness, and batch-to-batch consistency under physiologically relevant conditions. Material integrity and H₂-release performance must also be maintained during sterilization, storage, packaging, and manufacturing scale-up.

Translational barriers for material-based hydrogen therapy

Most hydrogen-releasing biomaterials have been evaluated in cellular systems or small-animal models of cancer, intestinal inflammation, ischemic injury, osteoarthritis, and wound repair. These studies commonly demonstrate improved targeting or prolonged hydrogen generation, but often measure release in simplified buffers rather than within the target tissue. Pathological variables such as heterogeneous pH, limited perfusion, protein adsorption, substrate depletion, and immune-cell uptake may substantially change material performance in vivo. Another barrier is the increasing complexity of multifunctional nanoplatforms. A single system may generate H₂ while releasing metal ions, consuming glutathione, producing heat or ROS, carrying a drug, or activating immune responses. Although such combinations can produce strong therapeutic effects, they make it difficult to determine whether H₂ is essential to the outcome. Factorial controls and non-hydrogen-generating analogues are needed to establish the contribution of each component.

Material-based H₂ nanosystem also requires comparison with simpler alternatives. A hydrogen-generating nanoparticle should demonstrate a clear advantage over inhalation, HRW, HRS, or standard treatment in terms of localization, duration, efficacy, or treatment burden. Many studies compare sophisticated materials only with untreated controls, making their added value difficult to assess. Progress is further limited by scarce large-animal studies, incomplete repeat-dose safety data, uncertain clearance, and administration procedures that may be impractical outside specialized research settings.

In addition, clinical translation of material-based H₂ therapy depends on a standardized framework for comparing H₂ exposure with that achieved by conventional administration. Because H₂ diffuses rapidly and is rapidly eliminated, the nominal material dose, H₂-loading capacity, or theoretical hydrogen yield does not adequately represent the biologically available dose. Future studies should distinguish among the administered material dose, total H₂ capacity, generation or release rate, amount of H₂ delivered, and exposure achieved within the target tissue. Where technically feasible, local concentration–time profiles should be characterized using validated methods and should include peak concentration, exposure duration, integrated exposure, and spatial distribution, together with clearly reported calibration and sampling procedures. Dose-ranging studies should relate these exposure measures to mechanistic biomarkers and functional outcomes to establish dose–exposure–response relationships. Clinical trials should use validated, indication-specific primary endpoints, prespecified assessment times, appropriate comparators, and clinically meaningful responder definitions. Pharmacodynamic biomarkers and imaging findings can support evidence of biological activity but should not substitute for patient-centered outcomes. Regulatory pathways will depend on the composition, intended use, and primary mode of action of each platform. An H₂-generating material and its associated activation or delivery device may therefore require evaluation as a drug, device, biological product, or combination product. Product identity, critical quality attributes, H₂-generation specifications, manufacturing controls, device performance, biocompatibility, degradation products, and long-term safety should be defined early in development.

Future perspectives for material-based hydrogen therapy

Future development should prioritize diseases in which local and sustained H₂ generation provides a clear therapeutic advantage. Solid tumors, ischemic lesions, inflammatory bowel disease, osteoarthritis, infected or chronic wounds, and perioperative tissue injury are promising because the target site is anatomically defined and can potentially be reached by an injectable, implantable, oral, or topical material. By contrast, complex nanomaterials may offer limited benefit for systemic conditions that can be treated more simply with HRW or inhalation. Moreover, material design should emphasize controllable hydrogen production, biodegradability, and disease-specific activation. Microenvironment-responsive systems can exploit local acidity, ROS, enzymes, or metabolic substrates, whereas externally triggered platforms can provide temporal control through light, ultrasound, or electrical stimulation. However, additional functions should be incorporated only when they provide a clear therapeutic or monitoring benefit. A relatively simple biodegradable material with reproducible release may be more suitable for further development than a highly multifunctional platform whose efficacy depends on several poorly separable mechanisms.

Preclinical studies of material-based hydrogen therapy should verify and quantify H₂ generation within the target tissue and establish its relationship to therapeutic outcomes. Experiments should use clinically realistic administration, relevant disease stages, both sexes, older animals where appropriate, and comorbidities that may influence material distribution or degradation. Promising platforms should subsequently be evaluated in large-animal models, with particular attention to local tissue reactions, systemic distribution, clearance, repeat-dose toxicity, and long-term functional outcomes. Direct comparison with conventional H₂ delivery and current standard treatment should be incorporated early.

The next generation of material-based hydrogen therapy may combine controlled H₂ production with imaging, disease-specific targeting, or biomarker-guided patient selection. Multi-omics approaches may help identify redox, metabolic, or immune signatures associated with treatment response, but candidate biomarkers require targeted experimental validation[38,39]. Ultimately, progress will depend on selecting appropriate diseases, simplifying material design, demonstrating hydrogen-dependent efficacy, and developing systems that are reproducible, biodegradable, and suitable for clinically practical administration.

Conclusion

H₂ is increasingly understood as a context-dependent regulator of cellular stress rather than solely as a direct radical scavenger. Its biological effects involve selective attenuation of highly reactive oxygen and nitrogen species, activation of endogenous antioxidant defenses, preservation of mitochondrial homeostasis, suppression of NF-κB/NLRP3-mediated inflammation, regulation of programmed cell death, and modulation of host-microbial interactions. These interconnected mechanisms provide a plausible basis for the protective effects observed across diverse disease models, although the initiating molecular targets and determinants of treatment response remain incompletely defined.

An important advance in the field is the transition from conventional inhalation and hydrogen-rich fluids to materials-enabled delivery. Hydrogen-carrying nanosystems, in situ hydrogen-generating biomaterials, stimulus-responsive nanoplatforms, and biological production systems can prolong local H₂ availability and improve spatial and temporal control. These approaches are particularly promising for anatomically defined lesions, including solid tumors, ischemic tissues, intestinal inflammation, osteoarthritis, and chronic wounds. However, their therapeutic effects may also arise from carrier degradation, ion release, external stimulation, or accompanying treatments. Establishing the specific contribution of H₂ is therefore essential.

Although H₂ has demonstrated therapeutic potential in a broad range of experimental models, outcomes have varied across studies, and clinical evidence remains exploratory. Differences in H₂ exposure, treatment timing, disease stage, model characteristics, concurrent therapies, and outcome assessment currently limit reproducibility and cross-study comparison. Material-based hydrogen therapy is even earlier in development, with most studies limited to cellular and small-animal models. Future research should prioritize well-defined diseases in which localized or sustained hydrogen generation provides a clear advantage over conventional administration. Promising systems should combine controllable H₂ production, biodegradability, reproducible manufacturing, and acceptable long-term safety. Their efficacy should be confirmed in clinically relevant and large-animal models, directly compared with conventional H₂ delivery and standard treatment, and ultimately evaluated in well-controlled clinical trials. The future value of hydrogen therapy will depend not on achieving the highest hydrogen output or accumulating additional positive models, but on developing disease-specific interventions that are mechanistically attributable, safe, reproducible, and capable of improving outcomes relevant to patients.

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