Therapeutic effects of exosome‑based hyperin delivery in a cyclophosphamide‑induced mouse model of diminished ovarian...

The development of more effective and affordable strategies for the treatment of diminished ovarian reserve (DOR) is of notable importance due to its increasing prevalence in young patients and the limited efficacy of current clinical interventions in restoring fertility. The present study investigated the efficacy of umbilical cord‑derived mesenchymal stem cell (UCMSC)‑derived exosome‑based hyperin delivery in ameliorating cyclophosphamide (CP)‑induced DOR in mice, and elucidated the potential underlying mechanisms of resulting therapeutic benefits. Exosomes were isolated from UCMSCs and encapsulated with hyperin using ultrasonication. The DOR mouse model itself was established via treatment with CP; these model mice were then treated with hyperin, UCMSC‑exosome controls or hyperin‑encapsulated UCMSC‑exosomes. After treatment, body weight, estrous cycles and general health were monitored. Ovarian tissues were evaluated histologically, and serum levels of anti‑Müllerian hormone, follicle‑stimulating hormone and estradiol were measured via enzyme‑linked immunosorbent assay. Ovarian expression of the autophagy markers LC3 II, Beclin‑1 and P62 was analyzed via western blotting. CP treatment led to a notable deterioration in general health, body weight and ovarian function, as evidenced by altered estrous cycles and reduced follicle counts. Treatment with hyperin‑loaded UCMSC‑exosomes resulted in improvements in body weight, the restoration of estrous cycles. Notably, compared with the model group, mice treated with hyperin‑loaded UCMSC‑exosomes demonstrated increased primordial follicle counts and decreased atretic follicle counts. Treatment with hyperin‑loaded UCMSC‑exosomes modulated autophagic activity within the ovaries, with reduced LC3‑Ⅱ and beclin‑1 levels and increased P62 levels following treatment with hyperin‑loaded UCMSC‑derived exosomes. UCMSC‑derived exosomes loaded with hyperin effectively mitigated the adverse effects of CP on ovarian function, potentially via the modulation of autophagic processes. These findings supported the therapeutic potential of engineered exosomes for treating DOR, highlighting a novel approach for fertility preservation and reproductive medicine.