The platform, dubbed S-H/B, is built on hydrogenated silicon nanosheets, a material with a remarkable chemical trick. Unlike conventional hydrogen-storage compounds such as ammonia borane or metal borohydrides, which demand acidic conditions or catalysts to liberate their cargo, hydrogenated silicon nanosheets react spontaneously with water under ordinary physiological conditions, releasing hydrogen without known harmful byproducts. The researchers synthesized these nanosheets from calcium disilicide, treated them with hydrochloric acid at minus 25 degrees Celsius for seven days, and dispersed them by ultrasonication. The trouble with uncoated nanosheets, however, is that they release their hydrogen far too quickly for a chronic condition like reproductive aging, which calls for prolonged, low-maintenance exposure rather than a brief burst.

To solve this, the team wrapped the nanosheets in a custom polymer coating composed of polylactic acid fused with aldehyde-functionalized hyperbranched polyglycerol, abbreviated PLA-HPG-al. The design is elegant in its dual functionality. The hydrophobic polylactic acid segment acts as a molecular raincoat, restricting water’s access to the silicon core and thereby slowing the hydrolysis reaction that generates hydrogen. Meanwhile, the aldehyde groups on the polyglycerol branches form dynamic Schiff-base linkages with amine groups on tissue proteins, effectively gluing the nanoparticles to the scrotal tissue and preventing their clearance through lymphatic drainage. Spectroscopic analysis confirmed the coating, with characteristic silicon-hydrogen bands and an aldehyde-associated feature appearing together in the composite material, and electron microscopy showed the nanosheets retained their ultrathin morphology.

The performance data were compelling. In buffered solution at body temperature, uncoated nanosheets released roughly 66 percent of their total hydrogen capacity within just four hours. The coated version, by contrast, released only about 31 percent over 72 hours—a dramatic deceleration that transforms a flash of gas into a sustained therapeutic trickle. In cell-free assays, both formulations efficiently scavenged two of the most destructive reactive species implicated in reproductive aging: the hydroxyl radical, a major contributor to sperm DNA fragmentation, and peroxynitrite, a potent oxidant that accumulates in aged Sertoli cells. When Sertoli cells were challenged with these oxidants in the laboratory, treatment with the nanomaterials lifted cell viability from around 20 percent to between 70 and 75 percent, with no detectable toxicity at any tested concentration.

Bioadhesion proved equally important in living animals. When fluorescently labeled formulations were injected into the scrotum of 18-month-old mice, the bioadhesive version retained approximately 40 percent of its initial signal after 30 days, while a non-adhesive control formulation dropped below 30 percent within just 15 days. Ex vivo, the adhesive coating showed more than three times the binding to testicular tissue compared with the non-adhesive alternative. Safety testing in young mice revealed no significant changes in body weight, liver enzymes, or testicular and epididymal histology over a 30-day period, providing early reassurance about the platform’s biocompatibility.

The therapeutic results in naturally aged mice were striking. A single bilateral intrascrotal injection of S-H/B partially reversed testicular atrophy, raising the testicular index from about 5.0 to 6.3. Microscopy revealed less distortion and shrinkage of the seminiferous tubules, the production lines of sperm manufacturing. Immunostaining showed that the number of germ cells, proliferating cells, and meiotic cells roughly doubled compared with untreated aged mice. Most remarkably, epididymal sperm concentration more than doubled, progressive motility improved in parallel, and the proportion of abnormally shaped sperm fell from approximately 50 percent to 25 percent. No pathological changes appeared in the heart, liver, spleen, lung, or kidney.

To understand how the platform works at the cellular level, the researchers turned to single-cell RNA sequencing, resolving eight distinct testicular cell populations. The analysis delivered a surprise: more than 90 percent of all differentially expressed genes after treatment appeared in somatic cells rather than germ cells, with Sertoli cells—the metabolic caretakers of the seminiferous epithelium—showing the strongest response. Gene set enrichment analysis revealed activation of glycolysis pathways, hypoxia responses, and targets of hypoxia-inducible factor 1 alpha, or HIF-1α, a master transcriptional regulator of cellular metabolism. Crucially, HIF-1α messenger RNA levels were unchanged, while the protein itself became more abundant and more stable, pointing to post-translational regulation rather than altered gene expression.

The mechanistic chain the team assembled is intricate but coherent. Peroxynitrite, they found, can act as an alternative oxygen donor at the catalytic iron center of prolyl hydroxylase domain protein 1, or PHD1, the enzyme that tags HIF-1α for destruction. By scavenging peroxynitrite, the hydrogen released from S-H/B deprives PHD1 of its oxygen supply, slowing HIF-1α hydroxylation and protecting the protein from proteasomal degradation. Stabilized HIF-1α then translocates to the nucleus and switches on a battery of glycolytic genes, including glucose transporters GLUT1 and GLUT3 and enzymes such as hexokinase 2 and pyruvate kinase. Metabolic flux measurements confirmed increased glycolytic activity, and lactate production rose accordingly. This matters because Sertoli cells export lactate as the preferred fuel for developing germ cells, and lactate supplementation has previously been shown to reduce germ cell apoptosis and support spermatogenesis.

Causality was tested rigorously. When the researchers blocked HIF-1α with a pharmacological inhibitor or genetic knockdown, the benefits of S-H/B vanished: glycolytic enzymes fell, lactate production dropped, and in aged mice the improvements in testicular architecture, sperm concentration, motility, and morphology were largely abolished. Conversely, inhibiting PHD1 reproduced the effect of the nanoplatform, while knocking down PHD2, PHD3, or factor inhibiting HIF-1 did not, pinpointing PHD1 as the critical node. An in vitro hydroxylation assay using purified HIF-1α protein confirmed that peroxynitrite drives hydroxylation at the Pro564 site in a PHD1-dependent manner, and that this effect is blunted when peroxynitrite is scavenged.

The study represents a proof of concept rather than a ready-made therapy, and the authors are candid about the hurdles ahead. The work was conducted exclusively in naturally aged mice, and effects on actual reproductive outcomes—pregnancy rates, live births, and offspring health—remain untested. Intrascrotal injection has clinical precedent in procedures such as hydrocele sclerotherapy, but optimal dosing, injection protocols, and the degradation and clearance of the polymer coating in humans are unknown. Formulation stability poses another challenge, since water-responsive materials risk premature hydrogen generation during storage. Still, the concept of a single injection sustaining localized hydrogen delivery for a month, with a clearly defined molecular mechanism running from gas scavenging through metabolic reprogramming to restored sperm production, marks a genuinely novel convergence of materials chemistry and reproductive biology. If the findings translate beyond mice, sticky nanosheets could one day offer aging men something testosterone therapy cannot: a way to protect the sperm factory itself.

Subject of Research: A bioadhesive hydrogen-delivering nanoplatform for treating age-associated testicular dysfunction

Article Title: An intrascrotal bioadhesive nanoplatform for sustained hydrogen delivery ameliorates age-associated testicular dysfunction

Article References: Liang, S., Lv, J., Li, Z., Li, Z., Jiang, J., Yu, S., Wang, C., Wang, X., Xiao, L., & Yu, G. (2026). An intrascrotal bioadhesive nanoplatform for sustained hydrogen delivery ameliorates age-associated testicular dysfunction. Materials Today Bio, 41, Article 103732. https://doi.org/10.1016/j.mtbio.2026.103732

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103732

Keywords: molecular hydrogen, testicular aging, Sertoli cells, HIF-1α, peroxynitrite, nanoplatform, bioadhesive, spermatogenesis, oxidative stress, PHD1, glycolysis, hydrogenated silicon nanosheets