Hydrogen-generating nanomodulators for metabolic repair and functional recovery in ovarian tissue transplantation

Ischemia-reperfusion (I/R) injury occurring during ovarian tissue cryopreservation and transplantation (OTC-T) induces mitochondrial dysfunction and oxidative stress, leading to pronounced follicular loss and compromised graft performance-key challenges that limit transplantation success. Here, we present a hydrogen-releasing nanomodulator composed of potassium borohydride nanoparticles embedded within a thermosensitive hydrogel (KBH₄@Gel), designed to achieve sustained in situ hydrogen (H₂) generation for metabolic repair and ovarian function restoration. Upon local administration, the thermosensitive gel undergoes a sol-gel transition, encapsulating KBH₄ nanoparticles and enabling controlled H₂ release under mildly acidic, ischemia-mimicking conditions. Compared with free KBH₄ nanoparticles, KBH₄@Gel exhibits refined release kinetics and extended H₂ bioavailability, thereby providing long-term antioxidative protection. Mechanistic investigations demonstrate that KBH₄@Gel efficiently scavenges reactive oxygen species (ROS), preserves mitochondrial architecture, promotes angiogenesis at the graft site, and enhances ATP synthesis, ultimately reducing primordial follicle apoptosis and improving graft viability. This study introduces a precise and durable nanotherapeutic platform for metabolic repair and functional recovery in ovarian tissue transplantation, offering a broadly translatable strategy to mitigate I/R-induced injury across reproductive and other ischemic tissues.