An intrascrotal bioadhesive nanoplatform for sustained hydrogen delivery ameliorates age-associated testicular dysfunction.

Testicular aging is characterized by progressive spermatogenic decline. Accumulating oxidative injury and insufficient metabolic support from Sertoli cells may contribute to this process. Although molecular hydrogen has shown antioxidant potential, its therapeutic application in reproductive aging is limited by rapid dissipation after administration. To overcome this barrier, we developed the localized hydrogen-releasing system S-H/B. This platform integrates hydrogenated silicon nanosheets (S-H) with a bioadhesive polymer, aldehyde-functionalized polylactic acid-hyperbranched polyglycerol (PLA-HPG-al). The resulting formulation adhered to peritesticular tissue following intrascrotal injection, showed prolonged local retention, and enabled sustained hydrogen release under physiological conditions. This sustained local hydrogen delivery reduced age-associated testicular degeneration and promoted spermatogenesis in aged mice. Notably, single-cell RNA sequencing revealed enhanced HIF-1 signaling and glycolysis-related transcriptional programs in aged Sertoli cells following S-H/B treatment. Further mechanistic analyses indicated that S-H/B reduced ONOO- levels and limited PHD1-dependent HIF-1α hydroxylation, thereby slowing HIF-1α degradation and promoting its nuclear localization. Consistently, S-H/B increased glycolytic enzyme expression, glucose uptake, glycolytic flux, and lactate production in Sertoli cells, whereas HIF-1α inhibition attenuated these metabolic changes. The increased lactate production may have contributed to improved seminiferous epithelial function. Overall, this work presents a bioadhesive hydrogen delivery strategy for age-associated male reproductive dysfunction and suggests that metabolic remodeling in Sertoli cells may contribute to its beneficial effects.